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Structure-wise discrimination of adenine and guanine by proteins on the basis of their nonbonded interactions a
S. Usha & S. Selvaraj
a
a
Department of Bioinformatics, School of Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamilnadu, India Published online: 23 Sep 2014.
Click for updates To cite this article: S. Usha & S. Selvaraj (2015) Structure-wise discrimination of adenine and guanine by proteins on the basis of their nonbonded interactions, Journal of Biomolecular Structure and Dynamics, 33:7, 1474-1492, DOI: 10.1080/07391102.2014.958759 To link to this article: http://dx.doi.org/10.1080/07391102.2014.958759
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Journal of Biomolecular Structure and Dynamics, 2015 Vol. 33, No. 7, 1474–1492, http://dx.doi.org/10.1080/07391102.2014.958759
Structure-wise discrimination of adenine and guanine by proteins on the basis of their nonbonded interactions S. Usha and S. Selvaraj* Department of Bioinformatics, School of Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamilnadu, India Communicated by Ramaswamy H. Sarma
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(Received 27 May 2014; accepted 22 August 2014) We have analyzed the nonbonded interactions of the structurally similar moieties, adenine and guanine forming complexes with proteins. The results comprise (a) the amino acid–ligand atom preferences, (b) solvent accessibility of ligand atoms before and after complex formation with proteins, and (c) preferred amino acid residue atoms involved in the interactions. We have observed that the amino acid preferences involved in the hydrogen bonding interactions vary for adenine and guanine. The structural variation between the purine atoms is clearly reflected by their burial tendency in the solvent environment. Correlation of the mean amino acid preference values show the variation that exists between adenine and guanine preferences of all the amino acid residues. All our observations provide evidence for the discriminating nature of the proteins in recognizing adenine and guanine. Keywords: purines; protein–purine; adenine and guanine; nonbonded interactions; residue preferences
Introduction The high degree of specificity of similar ligand moieties provides us a platform to explore the mechanism of molecular recognition for drug target discovery and inhibitor design. The three-dimensional structures of protein-ligand complexes give us a detailed knowledge of the various nonbonded interactions between protein and ligand atoms which in turn helps us to understand the discrimination of proteins among similar ligands. Adenine and guanine which are similar structures differ by a nitrogenous and oxygen group. The identification of specific sequences or structural motifs that recognize and discriminate adenine and guanine is essential for the prediction of binding sites and functions of unknown proteins that utilize adenine or guanine nucleotides (Zhao, Morris, Olson, & Goodsell, 2001). These authors presented a grid-based method for deriving recognition templates from a set of diverse nucleotide-binding proteins that reveal the basis of specific binding of adenylate, including shape complementarity, hydrogen bonds, and key steric contact for excluding guanylate from adenylate-specific sites. Thornton and coworkers have described the differences in hydrogen-bonding patterns, the preference for interacting amino acids and the burial tendency in protein molecules between adenine and guanine and suggested that there exists a ‘fuzzy clustering’ of interactions in the nucleotide-binding sites with no clear common discriminatory motif for the two nucleotides (Nobeli, Laskowski, Valdar, & Thornton, 2001). Moodie, *Corresponding author. Email: [email protected] © 2014 Taylor & Francis
Mitchell, and Thornton (1996) in their study of adenylate-binding proteins have shown that hydrogen bonding and shape allow specific recognition of adenine and not guanine. Basu, Sivanesan, Kawabata, and Go (2004) have demonstrated that electrostatic potential is an excellent indicator for discrimination between adenine and guanine-specific binding sites in proteins. Saito, Go, and Shirai (2006) constructed an empirical approach for detecting nucleotide-binding sites on proteins by examining the protein structures in the protein data bank (PDB). Kahraman, Morris, Laskowski, Favia, and Thornton (2010) carried out a detailed investigation and showed the diversity of physicochemical environment experienced by identical ligands in the binding pockets of unrelated proteins. Firoz et al. (2011) have explored how single amino acid propensities play a role in the affinity and specificity by investigating the residue preferences for adenine and guanine phosphates. In our recent study, we have analyzed the structural discrimination of the three pyrimidine bases, cytosine, thymine, and uracil by proteins in terms of their nonbonded interactions. Based on our analysis, we have shown the discrimination of cytosine by arginine contacts and thymine by its distinct behavior in the solvent environment (Usha & Selvaraj, 2014). In the present work, we have done a similar study of the purine basal structures, adenine and guanine (Figure 1) that form complexes with proteins. We have made use of the information of the PDBe database (Velankar et al., 2010) which specifies all the nonbonded
Structure-wise discrimination of adenine and guanine by proteins on the basis of their nonbonded interactions
1475
Results The purine bases adenine and guanine resemble each other in their structures. In the present study, we have attempted to understand the discrimination of these molecules by proteins in terms of nonbonded interactions, ligand atom-residue preferences, and SASA of ligand atoms before and after complex formation with proteins.
Figure 1.
Structures of adenine and guanine bases.
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interactions of the ligand and protein atoms for the proteins available in the PDB (Berman et al., 2000) to analyze the atom-wise interactions of adenine- and guanine-containing ligands with proteins. Materials and methods Structural information of nonredundant proteins (less than 30% sequence identity) that interact with adenineand guanine-containing ligands was taken from the PDB (Berman et al., 2000). We have chosen 159 adenine- and 136 guanine-protein complexes (not forming complexes with DNA or RNA) which have X-ray resolution ≤ 2.0 Å. Only the interactions of the base atoms were accounted. The PDBe database (http://www.ebi.ac.uk/pdbe-site/ PDBeMotif/) provides information of the various nonbonded interactions that exist between the protein and the ligand (Velankar et al., 2010). The images of pi interactions have been obtained from the Pose View server (Stierand & Rarey, 2010) available in the PDB. The solvent accessible surface area (SASA) of the base atoms for both the uncomplexed form and complexed form were found out using the Ligand-Protein Contacts server (http://ligin.weizmann.ac.il/) (Sobolev, Sorokine, Prilusky, Abola, & Edelman, 1999). The details of all the interactions analyzed in the present work have been provided in our earlier paper along with their interaction criteria (Usha & Selvaraj, 2014). The mean values for the number of ligand atom–amino acid residue contacts for each type of interactions are computed and normalized to percentage values. To know the relative preference of all the amino acid residues between adenine and guanine bases, (i) the correlation coefficients of the corresponding nonbonded interactions between adenine and guanine with all the interacting amino acid residues of proteins and (ii) the correlation of the mean amino acid preference values (%) of all the interacting amino acid residues between the corresponding adenine and guanine atoms were computed. The details regarding the selected data-set complexes, viz. PDB ID, their functional classification, pH, X-ray resolution (Å), ligand ID, the representative chain and ligand name, are provided in the Annexure.
Nonbonded interactions The protein–purine interactions are studied in terms of van der Waals, hydrogen bond, plane-atom, plane-plane, and other undefined interactions (within 5 Å). The significant contacts (top three most favored amino acid residues) in each type of interactions are as follows: van der Waals interactions Phenylalanine forms the most favorable contact for both guanine (15.1%) and adenine (11.2%) bases through van der Waals interactions, followed by tryptophan (9.7%) and tyrosine (9.5%) in guanine contacts and tyrosine (8.4%) and arginine (8.0%) in adenine contacts (Figure 2(a)). Hydrogen bond interactions Aspartic acid (23.5%) is predominantly involved in hydrogen-bonding interactions with guanine followed by asparagine (15.7%) and glutamic acid (11.3%). Valine (11.2%), alanine, and isoleucine (9.6%) (through backbone N and O atoms) favor adenine contacts (Figure 2(b)). Plane-atom interactions Interactions between chemical planar structures and an atom are plane-atom interactions (Golovin & Henrick, 2008). Tryptophan (adenine: 31.9% and guanine: 38.6%) followed by phenylalanine (adenine: 31.4% and guanine: 30.5%) and tyrosine (adenine: 17.0% and guanine: 22.4%) form predominant contacts with both adenine and guanine through plane-atom interactions (Figure 2(c)). Plane-plane interactions Plane-plane interactions occur between chemical planar structures and between rings (Golovin & Henrick, 2008). Phenylalanine (34.5%) contacts with guanine are more significant as compared with adenine (22.7%) in the case of plane-plane interactions, followed by tryptophan (adenine: 19.2% and guanine: 23.0%) and tyrosine (adenine: 17.3% and guanine: 20.1%) (Figure 2(d)).
S. Usha and S. Selvaraj
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1476
Figure 2. Amino acid residue contacts with purine bases through (a) van der Waals, (b) hydrogen bond, (c) plane-atom, (d) planeplane, (e) undefined (5’)ADENYLYL(2’-
FLAVIN-ADENINE DINUCLEOTIDE
S-ADENOSYLMETHIONINE
LIGAND NAME
1488 S. Usha and S. Selvaraj
Signaling Protein Cell Cycle
1W5F
1WF3
1WUR
1XE7
1XQP
1Y0B
1YRB
2ATZ
2BLE
2CE2
2CXX
2DBY
30
31
32
33
34
35
36
37
38
39
40
1.7.1.7
2.4.2.22
3.2.2 4.2.99.18
3.5.4.16
Signaling Protein
Hydrolase
Oxidoreductase
Structural Genomics UNKNOWN FUNCTION
Hydrolase
Transferase
Lyase
Structural Genomics UNKNOWN FUNCTION
Hydrolase
Hydrolase
Cell Division
Methyltransferase
29
2.1.1.57
3.6.5
Hydrolase Signaling Protein Hydrolase
1TQ4
3.6.1
3.6.5.1
1V39
1SZ3
26
Hydrolase
Hydrolase (guanyloribonuclease)
Transferase
Transport Protein
Signaling Protein
Protein Transport
Lyase
Ligand Binding Protein
Oxidoreductase
Structural Protein
Hydrolase
27
1SVS
25
3.6.1.6
3.1.27.3
2.7.1.21
4.2.1.47
1.1.5.6
3.1
3.1.27.3
Transferase Hydrolase
Translation
28
1RGE
1QHI
22
1S1D
1Q3E
21
24
1PUJ
23
1NRJ
1N7H
18
19
1MKY
17
20
1KQF
16
Hydrolase
1IYB
1IPC
13
1JXM
RNA Binding Protein
1I0V
14
Transferase (glycosyltransferase)
1HGX
11
12
15
Hydrolase
1GOY
10
2.1.2.3 3.5.4.10
1G8M
Metal Binding Protein Transferase
1G7S
2.7.7.77
Signaling Protein
Transferase
Transferase
8
1F5N
5
2.7.4.8
2.4.2.8
9
1EX7
4
Phosphotransferase
Phosphoribosyltransferase
1FRW
1DQP
3
2.7.4.13
2.4.2.22
1FSG
1DEK
2
CLASSIFICATION
6
1A95
1
E. C. No.
7
PDB ID
S. No.
5.2
6.0
7.6
6.5
7.4
5.6
5.5
7.5
5.6
6.8
9.0
6.5
4.6
4.5
6.0
5.0
6.7
7.5
4.6
6.5
5.5
6.4
10.0
8.5
7.7
8.5
4.2
7.0
7.2
5.8
8.0
6.5
7.0
5.5
7.5
6.5
9.0
pH
Annexure List of proteins and ligands that form guanine–protein complexes
1.76
1.70
1.00
1.90
2.00
1.75
1.80
1.69
1.75
1.82
1.88
2.00
1.80
1.95
1.60
1.50
1.60
1.15
1.90
1.90
2.00
1.70
1.80
1.90
1.60
2.00
1.50
2.00
1.23
1.90
2.00
1.75
2.00
1.05
1.75
1.70
1.90
1.75
2.00
2.00
X-RAY RESOLUTION
GDP
GDP
GDP
5GP
DGT
GDP
G4P
8HG
GUN
8DG
GNP
G2P
M7G
GDP
GNP
GNP
GP2
2GP
BPG
PCG
GNP
GTP
GDP
GDP
MGD
5GP
5GP
MGP
2GP
5GP
3GP
G
GDP
9DG
GTP
GNP
5GP
IMG
DGP
GUN
LIGAND ID
A
A
X
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
C
CHAIN ID
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
2’-DEOXYGUANOSINE-5’-TRIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’,3’-TETRAPHOSPHATE
2’-DEOXY-8-OXOGUANOSINE
GUANINE
8-OXO-2’-DEOXYGUANOSINE-5’-TRIPHOSPHATE
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER
7N-METHYL-8-HYDROGUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
PHOSPHOMETHYLPHOSPHONIC ACID GUANOSYL ESTER
GUANOSINE-2’-MONOPHOSPHATE
9-(4-HYDROXYBUTYL)-N2-PHENYLGUANINE
CYCLIC GUANOSINE MONOPHOSPHATE
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
GUANOSINE-5’-TRIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE DINUCLEOTIDE
(Continued)
TETRAHYDRO-8-OXA -1,3,9,10-TETRAAZA-ANTHRACEN- 4-ONE
2-AMINO-5,6-DIMERCAPTO-7-METHYL-3,7,8A,9-
GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
7-METHYL-GUANOSINE-5’-TRIPHOSPHATE
GUANOSINE-2’-MONOPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-3’-MONOPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
9-DEAZAGUANINE
GUANOSINE-5’-TRIPHOSPHATE
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
GUANOSINE-5’-MONOPHOSPHATE
1,4-DIDEOXY-1,4-IMINO-1-(S)-(9-DEAZAGUANIN- 9-YL)-D-RIBITOL
2’-DEOXYGUANOSINE-5’-MONOPHOSPHATE
GUANINE
LIGAND NAME
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Structure-wise discrimination of adenine and guanine by proteins on the basis of their nonbonded interactions 1489
2ZEJ
2ZGY
2ZI7
2ZU9
3A6T
3B0X
74
75
76
77
78
79
2XJC
2XTM
73
2XI3
71
72
2XBU
2VKF
67
70
2V40
66
2WKQ
2RDE
65
2X2E
2QTH
69
2QM7
63
64
68
2PK3
2QCA
61
62
2PHN
60
Structural Protein RNA Binding Protein
2OH5
2OUU
58
2OGI
57
59
Hydrolase
2OGF
56
2.7.7.7
3.6.1.55
2.4.1.217
2.7.1.74
2.7.11.1
3.1.3.5
2.7.7.48
2.4.2.8
3.6.5.5
6.3.4.4
3.1.27.5
1.1.1.281
6.3.2.31 6.3.2.34
3.1.4.17 3.1.4.35
4.1.2.25
4.1.1.n1
2O74
Transferase
Hydrolase
Transferase
Transferase
Structural Protein
Transferase
Immune System
Hydrolase
Transferase
Transferase
Hydrolase
Transferase CELL ADHESION
Electron Transport
Ligase
Structural Genomics UNKNOWN FUNCTION
Nucleotide Binding Protein
Chaperone
Hydrolase
Oxidoreductase
Ligase
Hydrolase
Structural Genomics UNKNOWN FUNCTION
Lyase
Transferase
Translation
55
2.4.1.152
Hydrolase
2JGB
3.1.3
Transferase
2NZX
2JAO
52
2.7.7
Hydrolase Metal Binding Protein
Structural Genomics UNKNOWN FUNCTION
Hydrolase
Transport Protein
Transferase
Hydrolase
Lyase
Ribosome
Signaling Protein Translation
Hydrolase
CLASSIFICATION
53
2IRX
51
3.6
3.1 3.6.4.12
3.1.27.6
4.2.1.112
3.1
E. C. No.
(Continued).
54
2HF9
50
2FQX
47
2GJ8
2FC0
46
2HEK
2EA1
45
48
2E7Z
44
49
2DY1
2DYK
42
2DJH
41
43
PDB ID
S. No.
Annexure.
6.0
5.6
5.2
7.5
6.2
8.0
7.5
9.0
6.5
5.6
8.5
7.5
8.2
6.5
7.5
5.5
7.0
8.5
5.6
7.5
6.0
4.6
8.5
5.5
5.5
5.5
7.5
4.2
6.0
4.6
4.5
6.1
6.5
6.0
6.0
8.0
pH
1.36
1.96
2.00
1.97
1.90
2.00
1.70
2.00
1.70
1.80
2.00
1.60
1.70
1.90
1.92
2.00
1.85
1.82
1.35
1.52
1.98
1.85
1.89
1.80
1.90
1.70
2.00
1.80
1.90
2.00
1.70
1.70
2.00
1.80
1.26
1.96
1.60
1.90
X-RAY RESOLUTION
DGT
8OG
GDP
GNG
GDP
GDP
GDP
5GP
GTP
5GP
GDP
GTP
CF2
GDP
C2E
GDP
GDP
DGP
GDD
GDP
35G
GTP
GDP
OXG
GUN
GDP
MGT
DGP
GTP
GSP
GDP
GDP
GMP
DGP
GPG
MGD
GDP
GTP
3PD
LIGAND ID
A
A
A
B
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
A
A
B
A
A
A
A
A
A
A
A
A
A
A
A
CHAIN ID
2’-DEOXYGUANOSINE-5’-TRIPHOSPHATE
8-OXO-2’-DEOXY-GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
2’-DEOXY-GUANOSINE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
10(2H)-yl)ethyl]carbamoyl}guanosine
2’-deoxy-5’-O-{[2-(7,8-dimethyl-2,4-dioxo- 3,4-dihydrobenzo[g]pteridin-
GUANOSINE-5’-DIPHOSPHATE
2,9-diyl]bis (2-amino-1,9-dihydro-6H-purin- 6-one)
2H,7H-difuro[3,2-d:3’,2’-j] [1,3,7,9,2,8]tetraoxadiphosphacyclododecine-
tetrahydroxy-5,12-dioxidooctahydro-
9,9’-[(2R,3R,3aS,5S,7aR,9R,10R,10aS,12S,14aR)- 3,5,10,12-
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
2’-DEOXYGUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE-ALPHA-D-MANNOSE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-3’,5’-MONOPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
8-OXOGUANINE
GUANINE
GUANOSINE-5’-DIPHOSPHATE
7N-METHYL-8-HYDROGUANOSINE-5’-TRIPHOSPHATE
2’-DEOXYGUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
5’-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE
2’-DEOXYGUANOSINE-5’-MONOPHOSPHATE
GUANYLYL-2’,5’-PHOSPHOGUANOSINE
GUANOSINE DINUCLEOTIDE
TETRAHYDRO-8-OXA-1,3,9,10-TETRAAZA-ANTHRACEN- 4-ONE
2-AMINO-5,6-DIMERCAPTO-7-METHYL-3,7,8A,9-
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
1,9- DIHYDRO-6H-PURIN-6-ONE
2-AMINO-9-(2-DEOXY-3-O-PHOSPHONOPENTOFURANOSYL)-
LIGAND NAME
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1490 S. Usha and S. Selvaraj
2.4.1.57
3EVF
3EXM
3F47
3FUC
3GDH
3H2Y
3HV8
3KZZ
3LDU
3LLU
3M89
3MD7
3N1S
3NVW
3O0Q
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
3ZY2
4A7W
4AD6
116
117
118
Hydrolase
3ZPG
3ZR0
114
115
Viral Protein
3V9O
3ZBQ
112
2.7.6.3
2.7.4.22
2.4.1.221
3.6.1.55 3.6.1.56
1.1.1.193 3.5.4.26
Transferase
Transferase
Transferase
Hydrolase
Lyase
Oxidoreductase/oxidoreductase Substrate
Transferase
Transferase
Hydrolase
113
1.7.1.13
2.7.7.65
3.6.5.2
Transferase
3UXJ
108
2.4.1
Hydrolase
111
3T1O
107
3.1
Signaling Protein
3TDW
3SIW
106
Ligase Signaling Protein/inhibitor
3TVK
3RL4
105
6.3.3.3
Hydrolase
Transferase
Oxidoreductase
Oxidoreductase
Hydrolase
Hydrolase
Structural Protein
Hydrolase
Transferase
Transferase
Hydrolase
Hydrolase
Transferase
Transferase
Oxidoreductase
Hydrolase
Transferase
Transport Protein
Hydrolase
Transferase
109
3REG
104
1.17.1.4 1.17.3.2
3
2.1.1.63
3.1.4.52
2.1.1
2.4.2.1
1.12.98.2
3.6.1.6
2.1.1.56 2.1.1.57 2.7.7.48
3.2.2.5
Hydrolase
Signaling Protein
Transferase
110
3QXX
3QYY
103
3OKP
3E70
85
3PQC
3DZH
84
101
3DMH
83
102
1.17.4.1
3DEF
82
2.1.1
3C5H
81
2.7.13.3 2.7.4.6
3BBB
80
8
4.0
5.5
7.0
6.2
8.5
8.5
8.5
6.5
5.2
4.6
6.8
5.5
5.5
6.1
4.5
7.2
7.0
7.4
7.5
7.5
6.5
6.5
7.1
5.8
6.0
7.7
8.5
5.1
8.5
8.0
6.0
8.5
7.4
9.0
6.5
1.85
1.80
1.54
1.80
1.99
1.70
1.45
1.40
1.80
1.70
1.90
1.98
1.29
1.80
1.90
1.36
1.90
2.00
1.80
1.60
1.45
1.27
2.00
1.40
1.70
1.89
1.45
1.80
2.00
1.45
1.75
1.65
1.45
1.97
1.60
1.55
1.96
1.80
1.30
GSY
GTP
GDP
8OG
5GP
GDP
GUN
PRF
C2E
GDP
GDP
GDP
5GP
GSP
C2E
GDP
GDP
GDD
GDP
GUN
5GP
5GP
GSP
GNP
GTP
OBG
C2E
DGI
MGP
9DG
I2C
GP2
GTA
GDP
GTP
GMP
GDP
GNP
DG
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
C
J
A
A
A
A
A
A
A
A
A
A
A
A
C
A
A
A
A
B
7-(2-HYDROXYETHYL)-8-MERCAPTOGUANINE
GUANOSINE-5’-TRIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
8-OXO-2’-DEOXY-GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANINE
7-DEAZA-7-AMINOMETHYL-GUANINE
2,9-diyl]bis(2-amino-1,9-dihydro-6H-purin- 6-one)
(Continued)
2H,7H-difuro[3,2-d:3’,2’-j] [1,3,7,9,2,8]tetraoxadiphosphacyclododecine-
3,5,10,12-tetrahydroxy-5,12-dioxidooctahydro-
9,9’-[(2R,3R,3aS,5S,7aR,9R,10R,10aS,12S,14aR)-
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
5’-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE
tetraoxadiphosphacyclododecine- 2,9-diyl]bis(2-amino-1,9-dihydro-6H-purin- 6-one)
-5,12-dioxidooctahydro- 2H,7H-difuro[3,2-d:3’,2’-j][1,3,7,9,2,8]
9,9’-[(2R,3R,3aS,5S,7aR,9R,10R,10aS,12S,14aR)- 3,5,10,12-tetrahydroxy
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE-ALPHA-D-MANNOSE
GUANOSINE-5’-DIPHOSPHATE
GUANINE
GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
5’-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
GUANOSINE-5’-TRIPHOSPHATE
6-(benzyloxy)-9H-purin-2-amine
tetraoxadiphosphacyclododecine- 2,9-diyl]bis(2-amino-1,9-dihydro-6H-purin- 6-one)
3,5,10,12-tetrahydroxy -5,12-dioxidooctahydro- 2H,7H-difuro[3,2-d:3’,2’-j][1,3,7,9,2,8]
9,9’-[(2R,3R,3aS,5S,7aR,9R,10R,10aS,12S,14aR)-
2’-DEOXYGUANOSINE-5’-DIPHOSPHATE
7-METHYL-GUANOSINE-5’-TRIPHOSPHATE
9-DEAZAGUANINE
phosphoryl]guanosine
5’-O-[(S)-hydroxy{[2-hydroxy-3,5-dimethyl- 6-(2-oxoethyl)pyridin-4-yl]oxy}
PHOSPHOMETHYLPHOSPHONIC ACID GUANOSYL ESTER
P1-7-METHYLGUANOSINE-P3-ADENOSINE-5’,5’-TRIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
GUANOSINE
GUANOSINE-5’-DIPHOSPHATE
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
2’-DEOXYGUANOSINE-5’-MONOPHOSPHATE
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Structure-wise discrimination of adenine and guanine by proteins on the basis of their nonbonded interactions 1491
4E2V
123
4IEN
4LC4
4M53
134
135
136
4GMU
131
4H2W
4G0Z
130
4HJF
4FOJ
129
133
4EU0
128
132
4EMF
4ES5
126
127
4EDK
4DA6
122
4EI7
4BRG
121
125
4B46
124
4B2P
119
PDB ID
120
S. No.
Annexure.
3.1.2.20
6.2.1.n2
4.1.1.32
3.2.2.22
2.7.7
2.4.2.29
2.4.2.1
3.6.1.5
E. C. No.
(Continued).
Translation
Transferase
Hydrolase
Signaling Protein
Ligase
Lyase
Gene Regulation
Protein Binding
Signaling Protein
Transcription
Hydrolase
Replication
Transferase
Transferase/transferase Inhibitor
Transferase
Hydrolase
Structural Protein
Hydrolase
CLASSIFICATION
6.5
6.5
8.5
6.5
5.6
7.4
4.5
4.7
6.5
5.6
6.7
5.5
6.5
8.5
4.6
5.5
4
6.2
pH
2.00
1.70
2.00
1.75
1.95
1.20
1.75
1.55
1.70
1.80
1.77
1.90
2.00
1.18
1.70
1.45
1.90
1.60
X-RAY RESOLUTION
GCP
GMP
GDP
C2E
5GP
GTP
5GP
C2E
C2E
MGT
M7G
GDP
GTP
PRF
GA2
GNP
GDP
GTP
LIGAND ID
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
CHAIN ID
PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER
GUANOSINE
GUANOSINE-5’-DIPHOSPHATE
2,9-diyl]bis(2-amino-1,9-dihydro-6H-purin- 6-one)
2H,7H-difuro[3,2-d:3’,2’-j][1,3,7,9,2,8]tetraoxadiphosphacyclododecine-
3,5,10,12-tetrahydroxy-5,12-dioxidooctahydro-
9,9’-[(2R,3R,3aS,5S,7aR,9R,10R,10aS,12S,14aR)-
GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
2,9-diyl]bis(2-amino-1,9-dihydro-6H-purin- 6-one)
2H,7H-difuro[3,2-d:3’,2’-j][1,3,7,9,2,8]tetraoxadiphosphacyclododecine-
3,5,10,12-tetrahydroxy-5,12-dioxidooctahydro-
9,9’-[(2R,3R,3aS,5S,7aR,9R,10R,10aS,12S,14aR)-
(2-amino-1,9-dihydro-6H-purin- 6-one)
2H,7H-difuro [3,2-d:3’,2’-j][1,3,7,9,2,8]tetraoxadiphosphacyclododecine-2,9-diyl]bis
tetrahydroxy-5,12-dioxidooctahydro-
9,9’-[(2R,3R,3aS,5S,7aR,9R,10R,10aS,12S,14aR)- 3,5,10,12-
7N-METHYL-8-HYDROGUANOSINE-5’-TRIPHOSPHATE
7N-METHYL-8-HYDROGUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
7-DEAZA-7-AMINOMETHYL-GUANINE
9-(1,3-DIHYDROXY-PROPOXYMETHANE)GUANINE
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
LIGAND NAME
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1492 S. Usha and S. Selvaraj
Journal of Biomolecular Structure and Dynamics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/tbsd20
Structure-wise discrimination of adenine and guanine by proteins on the basis of their nonbonded interactions a
S. Usha & S. Selvaraj
a
a
Department of Bioinformatics, School of Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamilnadu, India Published online: 23 Sep 2014.
Click for updates To cite this article: S. Usha & S. Selvaraj (2015) Structure-wise discrimination of adenine and guanine by proteins on the basis of their nonbonded interactions, Journal of Biomolecular Structure and Dynamics, 33:7, 1474-1492, DOI: 10.1080/07391102.2014.958759 To link to this article: http://dx.doi.org/10.1080/07391102.2014.958759
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Journal of Biomolecular Structure and Dynamics, 2015 Vol. 33, No. 7, 1474–1492, http://dx.doi.org/10.1080/07391102.2014.958759
Structure-wise discrimination of adenine and guanine by proteins on the basis of their nonbonded interactions S. Usha and S. Selvaraj* Department of Bioinformatics, School of Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamilnadu, India Communicated by Ramaswamy H. Sarma
Downloaded by [West Virginia University] at 07:35 03 May 2015
(Received 27 May 2014; accepted 22 August 2014) We have analyzed the nonbonded interactions of the structurally similar moieties, adenine and guanine forming complexes with proteins. The results comprise (a) the amino acid–ligand atom preferences, (b) solvent accessibility of ligand atoms before and after complex formation with proteins, and (c) preferred amino acid residue atoms involved in the interactions. We have observed that the amino acid preferences involved in the hydrogen bonding interactions vary for adenine and guanine. The structural variation between the purine atoms is clearly reflected by their burial tendency in the solvent environment. Correlation of the mean amino acid preference values show the variation that exists between adenine and guanine preferences of all the amino acid residues. All our observations provide evidence for the discriminating nature of the proteins in recognizing adenine and guanine. Keywords: purines; protein–purine; adenine and guanine; nonbonded interactions; residue preferences
Introduction The high degree of specificity of similar ligand moieties provides us a platform to explore the mechanism of molecular recognition for drug target discovery and inhibitor design. The three-dimensional structures of protein-ligand complexes give us a detailed knowledge of the various nonbonded interactions between protein and ligand atoms which in turn helps us to understand the discrimination of proteins among similar ligands. Adenine and guanine which are similar structures differ by a nitrogenous and oxygen group. The identification of specific sequences or structural motifs that recognize and discriminate adenine and guanine is essential for the prediction of binding sites and functions of unknown proteins that utilize adenine or guanine nucleotides (Zhao, Morris, Olson, & Goodsell, 2001). These authors presented a grid-based method for deriving recognition templates from a set of diverse nucleotide-binding proteins that reveal the basis of specific binding of adenylate, including shape complementarity, hydrogen bonds, and key steric contact for excluding guanylate from adenylate-specific sites. Thornton and coworkers have described the differences in hydrogen-bonding patterns, the preference for interacting amino acids and the burial tendency in protein molecules between adenine and guanine and suggested that there exists a ‘fuzzy clustering’ of interactions in the nucleotide-binding sites with no clear common discriminatory motif for the two nucleotides (Nobeli, Laskowski, Valdar, & Thornton, 2001). Moodie, *Corresponding author. Email: [email protected] © 2014 Taylor & Francis
Mitchell, and Thornton (1996) in their study of adenylate-binding proteins have shown that hydrogen bonding and shape allow specific recognition of adenine and not guanine. Basu, Sivanesan, Kawabata, and Go (2004) have demonstrated that electrostatic potential is an excellent indicator for discrimination between adenine and guanine-specific binding sites in proteins. Saito, Go, and Shirai (2006) constructed an empirical approach for detecting nucleotide-binding sites on proteins by examining the protein structures in the protein data bank (PDB). Kahraman, Morris, Laskowski, Favia, and Thornton (2010) carried out a detailed investigation and showed the diversity of physicochemical environment experienced by identical ligands in the binding pockets of unrelated proteins. Firoz et al. (2011) have explored how single amino acid propensities play a role in the affinity and specificity by investigating the residue preferences for adenine and guanine phosphates. In our recent study, we have analyzed the structural discrimination of the three pyrimidine bases, cytosine, thymine, and uracil by proteins in terms of their nonbonded interactions. Based on our analysis, we have shown the discrimination of cytosine by arginine contacts and thymine by its distinct behavior in the solvent environment (Usha & Selvaraj, 2014). In the present work, we have done a similar study of the purine basal structures, adenine and guanine (Figure 1) that form complexes with proteins. We have made use of the information of the PDBe database (Velankar et al., 2010) which specifies all the nonbonded
Structure-wise discrimination of adenine and guanine by proteins on the basis of their nonbonded interactions
1475
Results The purine bases adenine and guanine resemble each other in their structures. In the present study, we have attempted to understand the discrimination of these molecules by proteins in terms of nonbonded interactions, ligand atom-residue preferences, and SASA of ligand atoms before and after complex formation with proteins.
Figure 1.
Structures of adenine and guanine bases.
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interactions of the ligand and protein atoms for the proteins available in the PDB (Berman et al., 2000) to analyze the atom-wise interactions of adenine- and guanine-containing ligands with proteins. Materials and methods Structural information of nonredundant proteins (less than 30% sequence identity) that interact with adenineand guanine-containing ligands was taken from the PDB (Berman et al., 2000). We have chosen 159 adenine- and 136 guanine-protein complexes (not forming complexes with DNA or RNA) which have X-ray resolution ≤ 2.0 Å. Only the interactions of the base atoms were accounted. The PDBe database (http://www.ebi.ac.uk/pdbe-site/ PDBeMotif/) provides information of the various nonbonded interactions that exist between the protein and the ligand (Velankar et al., 2010). The images of pi interactions have been obtained from the Pose View server (Stierand & Rarey, 2010) available in the PDB. The solvent accessible surface area (SASA) of the base atoms for both the uncomplexed form and complexed form were found out using the Ligand-Protein Contacts server (http://ligin.weizmann.ac.il/) (Sobolev, Sorokine, Prilusky, Abola, & Edelman, 1999). The details of all the interactions analyzed in the present work have been provided in our earlier paper along with their interaction criteria (Usha & Selvaraj, 2014). The mean values for the number of ligand atom–amino acid residue contacts for each type of interactions are computed and normalized to percentage values. To know the relative preference of all the amino acid residues between adenine and guanine bases, (i) the correlation coefficients of the corresponding nonbonded interactions between adenine and guanine with all the interacting amino acid residues of proteins and (ii) the correlation of the mean amino acid preference values (%) of all the interacting amino acid residues between the corresponding adenine and guanine atoms were computed. The details regarding the selected data-set complexes, viz. PDB ID, their functional classification, pH, X-ray resolution (Å), ligand ID, the representative chain and ligand name, are provided in the Annexure.
Nonbonded interactions The protein–purine interactions are studied in terms of van der Waals, hydrogen bond, plane-atom, plane-plane, and other undefined interactions (within 5 Å). The significant contacts (top three most favored amino acid residues) in each type of interactions are as follows: van der Waals interactions Phenylalanine forms the most favorable contact for both guanine (15.1%) and adenine (11.2%) bases through van der Waals interactions, followed by tryptophan (9.7%) and tyrosine (9.5%) in guanine contacts and tyrosine (8.4%) and arginine (8.0%) in adenine contacts (Figure 2(a)). Hydrogen bond interactions Aspartic acid (23.5%) is predominantly involved in hydrogen-bonding interactions with guanine followed by asparagine (15.7%) and glutamic acid (11.3%). Valine (11.2%), alanine, and isoleucine (9.6%) (through backbone N and O atoms) favor adenine contacts (Figure 2(b)). Plane-atom interactions Interactions between chemical planar structures and an atom are plane-atom interactions (Golovin & Henrick, 2008). Tryptophan (adenine: 31.9% and guanine: 38.6%) followed by phenylalanine (adenine: 31.4% and guanine: 30.5%) and tyrosine (adenine: 17.0% and guanine: 22.4%) form predominant contacts with both adenine and guanine through plane-atom interactions (Figure 2(c)). Plane-plane interactions Plane-plane interactions occur between chemical planar structures and between rings (Golovin & Henrick, 2008). Phenylalanine (34.5%) contacts with guanine are more significant as compared with adenine (22.7%) in the case of plane-plane interactions, followed by tryptophan (adenine: 19.2% and guanine: 23.0%) and tyrosine (adenine: 17.3% and guanine: 20.1%) (Figure 2(d)).
S. Usha and S. Selvaraj
Downloaded by [West Virginia University] at 07:35 03 May 2015
1476
Figure 2. Amino acid residue contacts with purine bases through (a) van der Waals, (b) hydrogen bond, (c) plane-atom, (d) planeplane, (e) undefined (5’)ADENYLYL(2’-
FLAVIN-ADENINE DINUCLEOTIDE
S-ADENOSYLMETHIONINE
LIGAND NAME
1488 S. Usha and S. Selvaraj
Signaling Protein Cell Cycle
1W5F
1WF3
1WUR
1XE7
1XQP
1Y0B
1YRB
2ATZ
2BLE
2CE2
2CXX
2DBY
30
31
32
33
34
35
36
37
38
39
40
1.7.1.7
2.4.2.22
3.2.2 4.2.99.18
3.5.4.16
Signaling Protein
Hydrolase
Oxidoreductase
Structural Genomics UNKNOWN FUNCTION
Hydrolase
Transferase
Lyase
Structural Genomics UNKNOWN FUNCTION
Hydrolase
Hydrolase
Cell Division
Methyltransferase
29
2.1.1.57
3.6.5
Hydrolase Signaling Protein Hydrolase
1TQ4
3.6.1
3.6.5.1
1V39
1SZ3
26
Hydrolase
Hydrolase (guanyloribonuclease)
Transferase
Transport Protein
Signaling Protein
Protein Transport
Lyase
Ligand Binding Protein
Oxidoreductase
Structural Protein
Hydrolase
27
1SVS
25
3.6.1.6
3.1.27.3
2.7.1.21
4.2.1.47
1.1.5.6
3.1
3.1.27.3
Transferase Hydrolase
Translation
28
1RGE
1QHI
22
1S1D
1Q3E
21
24
1PUJ
23
1NRJ
1N7H
18
19
1MKY
17
20
1KQF
16
Hydrolase
1IYB
1IPC
13
1JXM
RNA Binding Protein
1I0V
14
Transferase (glycosyltransferase)
1HGX
11
12
15
Hydrolase
1GOY
10
2.1.2.3 3.5.4.10
1G8M
Metal Binding Protein Transferase
1G7S
2.7.7.77
Signaling Protein
Transferase
Transferase
8
1F5N
5
2.7.4.8
2.4.2.8
9
1EX7
4
Phosphotransferase
Phosphoribosyltransferase
1FRW
1DQP
3
2.7.4.13
2.4.2.22
1FSG
1DEK
2
CLASSIFICATION
6
1A95
1
E. C. No.
7
PDB ID
S. No.
5.2
6.0
7.6
6.5
7.4
5.6
5.5
7.5
5.6
6.8
9.0
6.5
4.6
4.5
6.0
5.0
6.7
7.5
4.6
6.5
5.5
6.4
10.0
8.5
7.7
8.5
4.2
7.0
7.2
5.8
8.0
6.5
7.0
5.5
7.5
6.5
9.0
pH
Annexure List of proteins and ligands that form guanine–protein complexes
1.76
1.70
1.00
1.90
2.00
1.75
1.80
1.69
1.75
1.82
1.88
2.00
1.80
1.95
1.60
1.50
1.60
1.15
1.90
1.90
2.00
1.70
1.80
1.90
1.60
2.00
1.50
2.00
1.23
1.90
2.00
1.75
2.00
1.05
1.75
1.70
1.90
1.75
2.00
2.00
X-RAY RESOLUTION
GDP
GDP
GDP
5GP
DGT
GDP
G4P
8HG
GUN
8DG
GNP
G2P
M7G
GDP
GNP
GNP
GP2
2GP
BPG
PCG
GNP
GTP
GDP
GDP
MGD
5GP
5GP
MGP
2GP
5GP
3GP
G
GDP
9DG
GTP
GNP
5GP
IMG
DGP
GUN
LIGAND ID
A
A
X
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
C
CHAIN ID
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
2’-DEOXYGUANOSINE-5’-TRIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’,3’-TETRAPHOSPHATE
2’-DEOXY-8-OXOGUANOSINE
GUANINE
8-OXO-2’-DEOXYGUANOSINE-5’-TRIPHOSPHATE
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER
7N-METHYL-8-HYDROGUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
PHOSPHOMETHYLPHOSPHONIC ACID GUANOSYL ESTER
GUANOSINE-2’-MONOPHOSPHATE
9-(4-HYDROXYBUTYL)-N2-PHENYLGUANINE
CYCLIC GUANOSINE MONOPHOSPHATE
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
GUANOSINE-5’-TRIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE DINUCLEOTIDE
(Continued)
TETRAHYDRO-8-OXA -1,3,9,10-TETRAAZA-ANTHRACEN- 4-ONE
2-AMINO-5,6-DIMERCAPTO-7-METHYL-3,7,8A,9-
GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
7-METHYL-GUANOSINE-5’-TRIPHOSPHATE
GUANOSINE-2’-MONOPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-3’-MONOPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
9-DEAZAGUANINE
GUANOSINE-5’-TRIPHOSPHATE
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
GUANOSINE-5’-MONOPHOSPHATE
1,4-DIDEOXY-1,4-IMINO-1-(S)-(9-DEAZAGUANIN- 9-YL)-D-RIBITOL
2’-DEOXYGUANOSINE-5’-MONOPHOSPHATE
GUANINE
LIGAND NAME
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Structure-wise discrimination of adenine and guanine by proteins on the basis of their nonbonded interactions 1489
2ZEJ
2ZGY
2ZI7
2ZU9
3A6T
3B0X
74
75
76
77
78
79
2XJC
2XTM
73
2XI3
71
72
2XBU
2VKF
67
70
2V40
66
2WKQ
2RDE
65
2X2E
2QTH
69
2QM7
63
64
68
2PK3
2QCA
61
62
2PHN
60
Structural Protein RNA Binding Protein
2OH5
2OUU
58
2OGI
57
59
Hydrolase
2OGF
56
2.7.7.7
3.6.1.55
2.4.1.217
2.7.1.74
2.7.11.1
3.1.3.5
2.7.7.48
2.4.2.8
3.6.5.5
6.3.4.4
3.1.27.5
1.1.1.281
6.3.2.31 6.3.2.34
3.1.4.17 3.1.4.35
4.1.2.25
4.1.1.n1
2O74
Transferase
Hydrolase
Transferase
Transferase
Structural Protein
Transferase
Immune System
Hydrolase
Transferase
Transferase
Hydrolase
Transferase CELL ADHESION
Electron Transport
Ligase
Structural Genomics UNKNOWN FUNCTION
Nucleotide Binding Protein
Chaperone
Hydrolase
Oxidoreductase
Ligase
Hydrolase
Structural Genomics UNKNOWN FUNCTION
Lyase
Transferase
Translation
55
2.4.1.152
Hydrolase
2JGB
3.1.3
Transferase
2NZX
2JAO
52
2.7.7
Hydrolase Metal Binding Protein
Structural Genomics UNKNOWN FUNCTION
Hydrolase
Transport Protein
Transferase
Hydrolase
Lyase
Ribosome
Signaling Protein Translation
Hydrolase
CLASSIFICATION
53
2IRX
51
3.6
3.1 3.6.4.12
3.1.27.6
4.2.1.112
3.1
E. C. No.
(Continued).
54
2HF9
50
2FQX
47
2GJ8
2FC0
46
2HEK
2EA1
45
48
2E7Z
44
49
2DY1
2DYK
42
2DJH
41
43
PDB ID
S. No.
Annexure.
6.0
5.6
5.2
7.5
6.2
8.0
7.5
9.0
6.5
5.6
8.5
7.5
8.2
6.5
7.5
5.5
7.0
8.5
5.6
7.5
6.0
4.6
8.5
5.5
5.5
5.5
7.5
4.2
6.0
4.6
4.5
6.1
6.5
6.0
6.0
8.0
pH
1.36
1.96
2.00
1.97
1.90
2.00
1.70
2.00
1.70
1.80
2.00
1.60
1.70
1.90
1.92
2.00
1.85
1.82
1.35
1.52
1.98
1.85
1.89
1.80
1.90
1.70
2.00
1.80
1.90
2.00
1.70
1.70
2.00
1.80
1.26
1.96
1.60
1.90
X-RAY RESOLUTION
DGT
8OG
GDP
GNG
GDP
GDP
GDP
5GP
GTP
5GP
GDP
GTP
CF2
GDP
C2E
GDP
GDP
DGP
GDD
GDP
35G
GTP
GDP
OXG
GUN
GDP
MGT
DGP
GTP
GSP
GDP
GDP
GMP
DGP
GPG
MGD
GDP
GTP
3PD
LIGAND ID
A
A
A
B
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
A
A
B
A
A
A
A
A
A
A
A
A
A
A
A
CHAIN ID
2’-DEOXYGUANOSINE-5’-TRIPHOSPHATE
8-OXO-2’-DEOXY-GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
2’-DEOXY-GUANOSINE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
10(2H)-yl)ethyl]carbamoyl}guanosine
2’-deoxy-5’-O-{[2-(7,8-dimethyl-2,4-dioxo- 3,4-dihydrobenzo[g]pteridin-
GUANOSINE-5’-DIPHOSPHATE
2,9-diyl]bis (2-amino-1,9-dihydro-6H-purin- 6-one)
2H,7H-difuro[3,2-d:3’,2’-j] [1,3,7,9,2,8]tetraoxadiphosphacyclododecine-
tetrahydroxy-5,12-dioxidooctahydro-
9,9’-[(2R,3R,3aS,5S,7aR,9R,10R,10aS,12S,14aR)- 3,5,10,12-
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
2’-DEOXYGUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE-ALPHA-D-MANNOSE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-3’,5’-MONOPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
8-OXOGUANINE
GUANINE
GUANOSINE-5’-DIPHOSPHATE
7N-METHYL-8-HYDROGUANOSINE-5’-TRIPHOSPHATE
2’-DEOXYGUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
5’-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE
2’-DEOXYGUANOSINE-5’-MONOPHOSPHATE
GUANYLYL-2’,5’-PHOSPHOGUANOSINE
GUANOSINE DINUCLEOTIDE
TETRAHYDRO-8-OXA-1,3,9,10-TETRAAZA-ANTHRACEN- 4-ONE
2-AMINO-5,6-DIMERCAPTO-7-METHYL-3,7,8A,9-
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
1,9- DIHYDRO-6H-PURIN-6-ONE
2-AMINO-9-(2-DEOXY-3-O-PHOSPHONOPENTOFURANOSYL)-
LIGAND NAME
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1490 S. Usha and S. Selvaraj
2.4.1.57
3EVF
3EXM
3F47
3FUC
3GDH
3H2Y
3HV8
3KZZ
3LDU
3LLU
3M89
3MD7
3N1S
3NVW
3O0Q
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
3ZY2
4A7W
4AD6
116
117
118
Hydrolase
3ZPG
3ZR0
114
115
Viral Protein
3V9O
3ZBQ
112
2.7.6.3
2.7.4.22
2.4.1.221
3.6.1.55 3.6.1.56
1.1.1.193 3.5.4.26
Transferase
Transferase
Transferase
Hydrolase
Lyase
Oxidoreductase/oxidoreductase Substrate
Transferase
Transferase
Hydrolase
113
1.7.1.13
2.7.7.65
3.6.5.2
Transferase
3UXJ
108
2.4.1
Hydrolase
111
3T1O
107
3.1
Signaling Protein
3TDW
3SIW
106
Ligase Signaling Protein/inhibitor
3TVK
3RL4
105
6.3.3.3
Hydrolase
Transferase
Oxidoreductase
Oxidoreductase
Hydrolase
Hydrolase
Structural Protein
Hydrolase
Transferase
Transferase
Hydrolase
Hydrolase
Transferase
Transferase
Oxidoreductase
Hydrolase
Transferase
Transport Protein
Hydrolase
Transferase
109
3REG
104
1.17.1.4 1.17.3.2
3
2.1.1.63
3.1.4.52
2.1.1
2.4.2.1
1.12.98.2
3.6.1.6
2.1.1.56 2.1.1.57 2.7.7.48
3.2.2.5
Hydrolase
Signaling Protein
Transferase
110
3QXX
3QYY
103
3OKP
3E70
85
3PQC
3DZH
84
101
3DMH
83
102
1.17.4.1
3DEF
82
2.1.1
3C5H
81
2.7.13.3 2.7.4.6
3BBB
80
8
4.0
5.5
7.0
6.2
8.5
8.5
8.5
6.5
5.2
4.6
6.8
5.5
5.5
6.1
4.5
7.2
7.0
7.4
7.5
7.5
6.5
6.5
7.1
5.8
6.0
7.7
8.5
5.1
8.5
8.0
6.0
8.5
7.4
9.0
6.5
1.85
1.80
1.54
1.80
1.99
1.70
1.45
1.40
1.80
1.70
1.90
1.98
1.29
1.80
1.90
1.36
1.90
2.00
1.80
1.60
1.45
1.27
2.00
1.40
1.70
1.89
1.45
1.80
2.00
1.45
1.75
1.65
1.45
1.97
1.60
1.55
1.96
1.80
1.30
GSY
GTP
GDP
8OG
5GP
GDP
GUN
PRF
C2E
GDP
GDP
GDP
5GP
GSP
C2E
GDP
GDP
GDD
GDP
GUN
5GP
5GP
GSP
GNP
GTP
OBG
C2E
DGI
MGP
9DG
I2C
GP2
GTA
GDP
GTP
GMP
GDP
GNP
DG
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
C
J
A
A
A
A
A
A
A
A
A
A
A
A
C
A
A
A
A
B
7-(2-HYDROXYETHYL)-8-MERCAPTOGUANINE
GUANOSINE-5’-TRIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
8-OXO-2’-DEOXY-GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANINE
7-DEAZA-7-AMINOMETHYL-GUANINE
2,9-diyl]bis(2-amino-1,9-dihydro-6H-purin- 6-one)
(Continued)
2H,7H-difuro[3,2-d:3’,2’-j] [1,3,7,9,2,8]tetraoxadiphosphacyclododecine-
3,5,10,12-tetrahydroxy-5,12-dioxidooctahydro-
9,9’-[(2R,3R,3aS,5S,7aR,9R,10R,10aS,12S,14aR)-
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
5’-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE
tetraoxadiphosphacyclododecine- 2,9-diyl]bis(2-amino-1,9-dihydro-6H-purin- 6-one)
-5,12-dioxidooctahydro- 2H,7H-difuro[3,2-d:3’,2’-j][1,3,7,9,2,8]
9,9’-[(2R,3R,3aS,5S,7aR,9R,10R,10aS,12S,14aR)- 3,5,10,12-tetrahydroxy
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE-ALPHA-D-MANNOSE
GUANOSINE-5’-DIPHOSPHATE
GUANINE
GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
5’-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
GUANOSINE-5’-TRIPHOSPHATE
6-(benzyloxy)-9H-purin-2-amine
tetraoxadiphosphacyclododecine- 2,9-diyl]bis(2-amino-1,9-dihydro-6H-purin- 6-one)
3,5,10,12-tetrahydroxy -5,12-dioxidooctahydro- 2H,7H-difuro[3,2-d:3’,2’-j][1,3,7,9,2,8]
9,9’-[(2R,3R,3aS,5S,7aR,9R,10R,10aS,12S,14aR)-
2’-DEOXYGUANOSINE-5’-DIPHOSPHATE
7-METHYL-GUANOSINE-5’-TRIPHOSPHATE
9-DEAZAGUANINE
phosphoryl]guanosine
5’-O-[(S)-hydroxy{[2-hydroxy-3,5-dimethyl- 6-(2-oxoethyl)pyridin-4-yl]oxy}
PHOSPHOMETHYLPHOSPHONIC ACID GUANOSYL ESTER
P1-7-METHYLGUANOSINE-P3-ADENOSINE-5’,5’-TRIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
GUANOSINE
GUANOSINE-5’-DIPHOSPHATE
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
2’-DEOXYGUANOSINE-5’-MONOPHOSPHATE
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Structure-wise discrimination of adenine and guanine by proteins on the basis of their nonbonded interactions 1491
4E2V
123
4IEN
4LC4
4M53
134
135
136
4GMU
131
4H2W
4G0Z
130
4HJF
4FOJ
129
133
4EU0
128
132
4EMF
4ES5
126
127
4EDK
4DA6
122
4EI7
4BRG
121
125
4B46
124
4B2P
119
PDB ID
120
S. No.
Annexure.
3.1.2.20
6.2.1.n2
4.1.1.32
3.2.2.22
2.7.7
2.4.2.29
2.4.2.1
3.6.1.5
E. C. No.
(Continued).
Translation
Transferase
Hydrolase
Signaling Protein
Ligase
Lyase
Gene Regulation
Protein Binding
Signaling Protein
Transcription
Hydrolase
Replication
Transferase
Transferase/transferase Inhibitor
Transferase
Hydrolase
Structural Protein
Hydrolase
CLASSIFICATION
6.5
6.5
8.5
6.5
5.6
7.4
4.5
4.7
6.5
5.6
6.7
5.5
6.5
8.5
4.6
5.5
4
6.2
pH
2.00
1.70
2.00
1.75
1.95
1.20
1.75
1.55
1.70
1.80
1.77
1.90
2.00
1.18
1.70
1.45
1.90
1.60
X-RAY RESOLUTION
GCP
GMP
GDP
C2E
5GP
GTP
5GP
C2E
C2E
MGT
M7G
GDP
GTP
PRF
GA2
GNP
GDP
GTP
LIGAND ID
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
CHAIN ID
PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER
GUANOSINE
GUANOSINE-5’-DIPHOSPHATE
2,9-diyl]bis(2-amino-1,9-dihydro-6H-purin- 6-one)
2H,7H-difuro[3,2-d:3’,2’-j][1,3,7,9,2,8]tetraoxadiphosphacyclododecine-
3,5,10,12-tetrahydroxy-5,12-dioxidooctahydro-
9,9’-[(2R,3R,3aS,5S,7aR,9R,10R,10aS,12S,14aR)-
GUANOSINE-5’-MONOPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
GUANOSINE-5’-MONOPHOSPHATE
2,9-diyl]bis(2-amino-1,9-dihydro-6H-purin- 6-one)
2H,7H-difuro[3,2-d:3’,2’-j][1,3,7,9,2,8]tetraoxadiphosphacyclododecine-
3,5,10,12-tetrahydroxy-5,12-dioxidooctahydro-
9,9’-[(2R,3R,3aS,5S,7aR,9R,10R,10aS,12S,14aR)-
(2-amino-1,9-dihydro-6H-purin- 6-one)
2H,7H-difuro [3,2-d:3’,2’-j][1,3,7,9,2,8]tetraoxadiphosphacyclododecine-2,9-diyl]bis
tetrahydroxy-5,12-dioxidooctahydro-
9,9’-[(2R,3R,3aS,5S,7aR,9R,10R,10aS,12S,14aR)- 3,5,10,12-
7N-METHYL-8-HYDROGUANOSINE-5’-TRIPHOSPHATE
7N-METHYL-8-HYDROGUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
7-DEAZA-7-AMINOMETHYL-GUANINE
9-(1,3-DIHYDROXY-PROPOXYMETHANE)GUANINE
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
GUANOSINE-5’-DIPHOSPHATE
GUANOSINE-5’-TRIPHOSPHATE
LIGAND NAME
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1492 S. Usha and S. Selvaraj
