The (biological) speciation of vanadate(V) as revealed by (51)V NMR: A tribute on Lage Pettersson and his work.

JIB-09637; No of Pages 7 Journal of Inorganic Biochemistry xxx (2014) xxx–xxx

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The (biological) speciation of vanadate(V) as revealed by 51V NMR: A tribute on Lage Pettersson and his work Dieter Rehder ⁎ Chemistry Department, University of Hamburg, Germany

a r t i c l e

i n f o

Available online xxxx Keywords: Vanadate Bioligands Speciation Potentiometry 51 V nuclear magnetic resonance

a b s t r a c t Four decades of research carried out by Lage Pettersson, his group and his coworkers are reviewed, research that has been directed predominantly towards the speciation of vanadate and systems containing, along with vanadate and co-reactants such as phosphate and peroxide, biologically relevant organics. In particular, those organics have been addressed that either are (potential) ligands for vanadate-derived coordination compounds generated at physiological conditions and/or function as constituents in medicinally interesting oxidovanadium compounds. Examples for molecules introduced in the context of the physiological vanadate–ligand interaction include the dipeptides Pro-Ala, Ala-Gly, Ala-His and Ala-Ser, the serum constituents lactate and citrate, and the nucleobases adenosine and uridine. The speciation in the vanadate–picolinate and vanadate–maltol systems is geared towards insulin-enhancing vanadium drugs. The speciation as a function of pH, ionic strength and the concentration of vanadate and the ligand(s) is based on potentiometric and 51V NMR investigations, a methodical combination that allows reliable access to composition, formation constants and, to some extent, also structural details for the manifold of species present in aqueous media at physiological pH and beyond. The time frame 1971 to 2014 is reviewed, emphasizing the interval 1985 to 2006, and thus focusing on biologically interesting vanadium systems. Figurative representations from the original literature have been included. © 2014 Elsevier Inc. All rights reserved.

1. Introduction

Lage Pettersson received his Ph.D. in Inorganic Chemistry in 1974 under the supervision of Nils Ingri at the University of Umeå in the North of Sweden. He continued to work in the Chemistry Department in Umeå, with his research focusing on the solution speciation and reactivity of inorganic and coordination compounds of molybdenum and vanadium. With respect to vanadium, his research activities increasingly addressed issues of biochemical and medicinal relevance. In order to

⁎ Tel.: +49 40 428386087. E-mail address: [email protected].

access the speciation within the aqueous vanadate(V) system as such, and vanadium(V)-based coordination compounds generated in the presence of (biogenic) ligands, Lage developed basic strategies in the application of 51V NMR spectroscopy, allowing for pivotal insight into, and perception of, vanadate–ligand interactions of biological relevance. He became appointed Professor of Chemistry at the Umeå University in 1999. Lage Pettersson, a tireless ally in the vanadium community, passed away in 2013 at the age of 73. My first encounter with Lage goes back to the 22nd International Conference on Coordination Chemistry (ICCC) in Budapest in 1982, where he presented a poster displaying the pH- and concentration-dependent speciation of vanadate in aqueous solutions, Fig. 1 [1,2]. Four years thereafter, I received a letter, stating that “… we have worked further with the H+-HVO2− system … [and] also studied 4 the vanadooxalate system. … The last three years we have focused on the molybdophosphate and molybdophenylphosphate systems. Having solved these, we plan to resume the study of the extremely complicated molybdovanadate system.” Lage's very first publications in fact describe details of the molybdophosphate systems [3,4], a topic which decades later he resumed in close cooperation with, inter alia, Masato Hashimoto from the Wakayama University [5], who also dedicated one of his recent papers (on chloridooxidoperoxidomolybdate) to Lage [6]. The last paper co-authored by Lage Pettersson, and published posthumously in 2014, once more addresses structural information on a molybdate system in aqueous solution [7]. For the molybdovanadates and molybdovanadophosphate systems mentioned in Lage's letter, and

http://dx.doi.org/10.1016/j.jinorgbio.2014.12.014 0162-0134/© 2014 Elsevier Inc. All rights reserved.

Please cite this article as: D. Rehder, The (biological) speciation of vanadate(V) as revealed by 51V NMR: A tribute on Lage Pettersson and his work, J. Inorg. Biochem. (2014), http://dx.doi.org/10.1016/j.jinorgbio.2014.12.014

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D. Rehder / Journal of Inorganic Biochemistry xxx (2014) xxx–xxx

Fig. 1. 51V NMR spectra of a ca. 0.31 M vanadate solution at different pH values. Chemical shifts relative to VOCl3 are indicated on the abscissa. Blue: the three signals of the three different vanadium centers Va, Vb and Vc in decavanadate HnV10O28(6-n)− (the dominant species at low pH; shown is the triprotonated form); red: monovanadate HnVO4(3-n)- (with decreasing pH this signal shifts to the left, indicated by a red arrow); green: [VO2(H2O)4]+. Spectra modified from ref. [1]. For the pH-dependence of the 51V shielding see also Fig. 2. (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)

investigated by multinuclear (31P, 51V, 95Mo) NMR plus potentiometry, see for example ref. [8,9]; for tungstovanadates ref. [10]. The greater part of Lage Pettersson's work focuses on a detailed analysis of the speciation in the vanadate system as a function of pH, the ionic strength and the presence of biogenic ligands. This work had in part been carried out in the frame of the European COST actions on “Metals in Proteins.” A main issue in these studies is 51V nuclear magnetic resonance, an analytical method that, combined with H+ potentiometric data, provides detailed insight into the speciation of the vanadate-based systems; Lage Pettersson has crucially contributed to the development and appreciation of this methodological approach. Correspondingly, and since this special issue is dedicated to the Vanadium Symposium, the present overview emphasizes Lage's input and share to the present level of awareness with respect to the speciation of vanadate and vanadium coordination compounds with biogenic ligands in media mimicking physiological conditions. EPR investigations, also sporadically carried out in Lage's group in view of the redox-lability of several of the systems (such as the vanadate–maltol system), as well as 17O, 95Mo and 183W NMR will not be addressed. Here, the interested reader is referred to, for example, refs. [8–11]. 2. Technical notes

the original literature have throughout been replaced by oxido, hydroxido and peroxido. 2.2. Species denotation In the original literature, the vanadate species characterized in solution are commonly denoted HpVqXrLs, where X represents O22−, and L is any ligand. Reference point is dihydrogenvanadate H2VO− 4 : (p,q,r,s) = (0,1,0,0). Examples for other species are as follows: HVO42− ≡ (−1,1,0,0) HVO2(O2)22− ≡ HVX22− ≡ (−1,1,2,0) V10O286− ≡ (4,10,0,0); according to the reaction for the formation of decavanadate(6−): 6− + 12H2O 4H+ + 10H2VO− 4 → V10O28

[VO(O2)2Pi]2 − ≡ (0,1,2,1); according to the following reaction equation: − → [VO(O2)2Pi]2 − + 3H2O; Pi− is the H2VO− 4 + 2H2O2 + Pi picolinato(1−) ligand

2.1. Nomenclature In order to adapt to IUPAC recommendations, the terms oxo, hydroxo and peroxo for the ligands O2 −, OH− and O22− employed in

In most instances discussed in the present overview, I have “translated” the HpVqXrLs descriptors employed in Pettersson's publications into formulae familiar to the majority of coordination chemists.



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3. The aqueous vanadate system, phosphovanadates and peroxidovanadates At very low concentrations (around 1 μM, and hence at concentrations of about the 20fold of human blood plasma), the only vanadate species present at ambient (i.e., physiological pH) are monohydrogenmonovanadate HVO42 − (pH N 8) and dihydrogen-monovanadate H2VO− 4 (pH 3–8). Below pH ≈ 2.5, the hydrated dioxidovanadium cation prevails, and in strongly alkaline media, vanadate VO43 − (orthovanadate) comes in. Orthovanadate can also be a constituent in minerals; the existence of metavanadate VO− 3 is restricted to the solid (mineralized) state. In the millimolar range, various vanadate condensation states co-exist. Fig. 2 provides a notion of the speciation of vanadate at an ionic strength of 0.6 M. Rapid acidification to pH 1.6 of a 40 mM vanadate solution gives rise to the formation of an additional transient tridecavanadate H12V13O403 −, Fig. 3, which decays with a half-life of 80 min [14]. At ambient physiological conditions, i.e., concentrations in the micromolar range, pH values around 7 and ionic strengths of approximately 0.15 M, the only vanadate of relevance is monovanadate HnVO4(3-n)−, where n at pH ≈ 7 is 2. Di- and, in particular, tetravanadate come in as vanadate concentrations increase locally; in (slightly) acidic environments (pH b 6), decavanadate is also an option. Vanadate can also interact with phosphate [15,16], forming phosphovanadates such as HnVPO7(4-n)−, where n at pH ≈ 7 is 1 and 2 (the pKa at an ionic strength of 0.15 M is 7.2). This phosphovanadate is by one to two orders of magnitude less stable against hydrolysis than divanadate, but six orders of magnitude more stable than diphosphate. In view of the rather high serum phosphate concentrations of 2.3 mM, phosphovanadates likely contribute to the physiological speciation of vanadium. Vanadate can also substitute for phosphate in the apatite of the bone structure. Bones in fact act as storage for vanadate, the rersidence time of which amounts to about a month. Vanadate is further a noteworthy species in the context of oxidative stress implemented by the reactive oxygen species peroxide O22− and

Fig. 3. 51V NMR spectrum of a freshly acidified vanadate solution. The signals b and c represent decavanadate and VO+ 2 , respectively, the signals a tridecavanadate. The sharp a signal to lower field (higher frequency) corresponds to the central tetrahedral vanadium 3− (hatched) of H12V13O40 , and the broader signal to higher field represents the peripheral pseudo-octahedrally coordinated vanadium ions. From ref. [14]; reproduced with permission, © American Chemical Society.

the hydrogenperoxide anion HO− 2 : On the one hand, peroxidovanadates such as H2VO3(O2)− and H2VO2(O2)− 2 can form [13], along with peroxidophosphovanadates; an example for the latter is HV(O2)O3(μ-O) PO33− [17]. On the other hand, vanadate also catalyzes the decomposition of peroxide and can thus be involved in Fenton-like reactions. 4. The interaction of vanadate with biogenic organic ligands Maltolato- and picolinatovanadium complexes have been investigated, mainly in the past about one-and-a-half decades, with respect

Fig. 2. Chemical shifts δ(51V) of the main vanadium(V) species present in aqueous solution as a function of pH at an ionic strength of 0.6 M Na(Cl). Formulas in the colors blue, green and red correspond to the framed species in Fig. 1. The dark blue octahedra in the decavanadates represent the three different vanadium species (Va, Vb and Vc in Fig. 1). Adapted from ref. [12] with kind permission of A. Gorzsás; see also ref. [13]. The inset shows the 51V NMR spectrum of a 5 mM vanadate solution at pH 5.7 at an ionic strength of 0.6 M Na(Cl). (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)


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Fig. 4. Three examples of complexes formed between vanadate and dipeptides. The notations provided in the original literature and the formation constants β are also shown. Refs.: vanadate/Pro-Ala [24], vanadate/Ala-Ser [25] and vanadate/Ala-His [26,27].

to their potential in the treatment of diseases, notably diabetes mellitus [18]. More generally, inorganic vanadate, as well as oxidovanadium (VO2+ · aq) and vanadium coordination compounds have been subjected to in vitro and in vivo tests aiming at the development of potential drugs for the treatment of cardio-vascular problems, tuberculosis, tropical diseases caused by parasites and cancer [19,20]. For all of these potential applications, the knowledge of the interaction of vanadate with serum constituents is of substantial interest, an assertion that also applies to a likely general beneficial role of vanadate through its function as a phosphate antagonist, as well as to the toxicity of vanadium when applied in non-physiologically high doses. This topic has thus been addressed by Lage Pettersson's group, in part in close cooperation with other groups in Europe, the US and Japan, and will be summarized and discussed in some detail in the following sub-sections. 4.1. Dipeptides When vanadate enters the blood stream, it is effectively taken up by serum proteins [21,22] such as transferrin (concentration in blood serum c ≈ 35 μM) and, to a sufficiently lesser extent, also by albumin (c ≈ 600 μM) and immunoglobulin G (c ≈ 84 μM). In addition, the free amino acids glycine (c ≈ 2.3 mM), histidine (80 μM), cysteine (30 μM), glutamate (60 μM) and tripeptide glutathione (3 μM) are around. Amino acids do not readily coordinate to vanadate; dipeptides, however, are efficient binders and have thus been employed to model (potential) coordination sites of vanadate in transferrin,

immunoglobulin and albumin. The dipeptides that had been investigated in Pettersson's group are Pro-Ala, Ala-Gly, Ala-His and Ala-Ser. Ala-His in particular is a good model for the interaction of vanadium species with transferrin (where, in all probability, His and Tyr are involved in vanadium binding), but also for the tight binding of vanadate to the histidine residue of phosphatases such as revealed for rat acid phosphatase [23]. Finally, histidine is one of the ligands coordinated to the vanadium center in vanadium-nitrogenase and the ligand that binds vanadate and peroxidovanadate in vanadate-dependent haloperoxidases. In Fig. 4, tentative structures of the peptide complexes and formation constants are displayed. These systems have been studied by a combination of 51V NMR and potentiometry. Fig. 5 is an illustrative example for the changes in species composition—here for the vanadate/Ala-His system—in the pH range 3.2 to 8.7. The ternary complexes formed between alanyl-histidine, vanadate and peroxide are sufficiently more stable than the binary vanadate–peptide complexes. With alanyl-histidine, the by far dominant species in the pH range of ca. 5–9 is the bisperoxido mono-ligand complex [VO(O2)2AlaHis]n− (n = 1, 2), Fig. 6. 4.2. Lactate, citrate and maltol Lactate and citrate are important monomolecular serum ingredients, the average concentrations of which in human blood serum amount to 1.5 (lactate) and 0.1 mM (citrate). Methylmaltol = 3-hydroxy-2-methyl-4pyrone, and ethylmaltol = 3-hydroxy-2-ethyl-4-pyrone, are not

Fig. 5. 51V NMR spectra of the ternary system H+–vanadate–alanyl-histidine (here abbreviated Ah; for the protonated species [VO2(AlaHis+)(H2O)]0 see the box). Complexes are framed mauve. The presentation of the spectra has been adapted from ref. [26]; © Acta Chem. Scand. For the vanadates V1, V2, V4 and V10 see Fig. 2.



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Fig. 6. Proposed structure for the dominant species formed between vanadate, peroxide and alanyl-histidine in 0.15 M Na(Cl) solution; from ref. [27]. Concentrations for the speciation diagram: c(vanadate) = 1 μM, c(H2O2) 10 μM, c(AlaHis) 20 mM. FV is the mole fraction. The speciation diagram has kindly been supplied by András Gorzsás, University of Umeå.

originally present in body fluids; oxidovanadium coordination compounds of these ligands (commonly abbreviated BMOV and BEOV, respectively) are however potential insulin-enhancing systems. BEOV has been shown, in phase IIa clinical tests, to reduce fasting glucose in diabetic subjects [18]. Maltol is a registered flavor component (EU) and food additive (US). Vanadate(V) readily forms complexes with maltol; at acidic conditions, however, reduction to oxidovanadium(IV) (“vanadyl”) complexes proceeds. The vanadate- and vanadyl complexes in the vanadate–methylmaltol system have been investigated in Lage Pettersson's group by potentiometry/51V NMR and by EPR, respectively [28]. In neutral to slightly alkaline solutions—and hence in blood serum with its pH of 7.4—reduction also occurs, although at a rather low rate, allowing for a detailed characterization of the vanadate–maltol system. The main species present in the approximately physiological pH range is [VO2(maltol)2]− (Fig. 7a), along with minor amounts of mono-ligate species. Lactate (Lac) complexation is favored in the acidic region only; complex formation at physiological pH is very weak. The dominant lactatovanadium(V) complexes present in slightly acidic media are the di- and trinuclear bis(ligand) complexes of overall composition V2(Lac)22 − and V3Lac23 − [29], where “V” is short for the oxido or dioxidovanadium center. At the physiological pH 7.4, VLac2 is the only existent species. The presence of peroxide somewhat shifts the range of stability towards the neutral to slightly alkaline pH range, with V2(O2)Lac2 (Fig. 7b) being the most abundant lactato species in the rather complex mixture. In the mixed ligand system vanadate/lactate/ citrate, a binuclear complex of composition V2CitLacn− (n = 2 and 3; Fig. 7c) has been identified in the acidic range. Binary vanadate–citrate

(a)

(b)

complexes in the physiological pH range are restricted to a species of composition V2Cit4− [30]. 4.3. Adenosine, uridine, imidazole and picolinate As insinuated above, vanadate and phosphate are structurally and electronically very similar, suggesting a role of vanadate in phosphatedependent (metabolic) pathways. The potential biological activity of adenosyl-vanadates, the vanadium analogs of adenosylphosphates, has thus initiated a series of studies directed towards the interaction between vanadate and adenosine in aqueous media, including imidazole (Im), one of the building units of adenosine (Ad). The main component in the approximate pH range 4–9 is a binuclear bisligand complex [{VO2Ad}2]2− [31], the structure of which, included in Fig. 8, had previously been reported [32]. In the ternary system vanadate–Ad-Im, a mononuclear complex [VO2Im(Ad)]− is detected at sufficiently high imidazole concentrations. The complexes show distinct signals in the 51 V NMR spectrum, the pattern of which reveals the presence of several isomers. The chemical shift induced by the {VO2(ribose)} moiety of the complex [{VO2Ad}2]2 −, ca. − 523 ppm, is very much the same as reported for the vanadate–inosine [33] and the vanadate–uridine [34] systems. For complexes formed in the ternary system vanadate– imidazole–peroxide, see also ref. [35]. In the light of promising in vivo screenings of the insulin-enhancing (type II diabetes) properties of vanadium complexes derived from 2-picolinate (pyridine-2-carboxylate) [36], 2,6-dipicolinates [37] and 2,5-dipicolinates [38], the Pettersson group has also carried out detailed studies into the vanadate–picolinate and vanadate–picolinate–peroxide systems [39]. Diabetes II is an outcome of insufficient response of the

(c)

Fig. 7. Proposed solution structures for oxidovanadium(V) complexes containing the ligands methylmaltolate (a), lactate and peroxide (b) and lactate plus citrate (c). The composition of the species shown has been derived from potentiometric plus 51V NMR studies mimicking about physiological conditions (pH ≈ 7 and ionic strength of 0.15 M). For references see text.


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Fig. 8. 51V NMR spectrum of a solution (0.5 mM NaCl) of vanadate + imidazole (in mauve) + adenosine (in red) with (top) and without (bottom) resolution enhancement. Spectra reproduced from ref. [31] with permission; © American Chemical Society.

cellular insulin receptor to insulin, leading to the dephosphorylation— initiated by a protein-tyrosine phosphatase (PTPase)—of the intracellular tyrosine subunits of the insulin receptor and consequently to the blocking of the cellular glucose uptake. Vanadate, peroxidovanadate and various vanadium complexes have been shown to counteract this dephosphorylation of the insulin receptor (likely by inhibiting the PTPase), and thus to restore glucose uptake. Complex formation between vanadate and picolinic acid/ picolinate(1−), Pi, takes place over a wide pH range (ca. 1.5 to 8.5). The dominant species in the pH range 3–7 are three isomers of VPi− 2 , − Fig. 9, with chemical shifts δ(51V) = −513 (VPi− 2 ), −530 ppm (*VPi2 ) and −553 (**VPi2− 2 ), with complex formation constants logβ around 18.5 [39]. In the most general sense, peroxide considerably enhances complex formation. This is also observed in the quaternary system H+/H2VO− 4 / H2O2/picolinate, where species distribution in the acidic to slightly alkaline regime is dominated by picolinato–peroxidovanadium complexes. For the most prominent complexes that form at about physiological pH and physiologically relevant vanadate concentrations after medication with vanadium compounds (~ 1 μM), the formation constants

logβ are 25.9 (for [VO(O2)Pi2]−, the main species in slightly acidic solutions, δ(51V) = − 632.2 ppm) and 16.7 (for [VO(O2)2Pi]−, the main species in slightly alkaline solutions, δ(51V) = − 744.8 ppm) [39]. Both species occur in several isomers; the formation constants and chemical shifts here provided are those for the predominant isomer. 5. Conclusions This brief review is dedicated to the work of Lage Pettersson, who was active as a Professor of Chemistry at the University of Umeå in Sweden. The review focuses on a brief account and overview of Lage's achievements in elucidating the speciation of vanadate in aqueous media. Based on solution studies into a multitude of vanadate–ligand interactions—work that has predominantly been carried out by a combination of potentiometry and 51V NMR spectroscopy—Pettersson's group has crucially contributed to the current scientific level of awareness with respect to systems that are of interest in the light of the speciation of the phosphate analogue vanadate in a biological context in general, and in human blood serum in particular. Depending on the concentration of the constituents and the pH (and, to some extent,

Fig. 9. Speciation diagram of the vanadate–picolinate–H+ system; c(vanadate) = 1 μM, c(Pi) = 20 mM. These concentrations represent conditions similar to the ones that may occur dur− ing possible drug administration, i.e., very low vanadium total concentrations with a very large excess of the ligand. Possible structures of the two main isomers, VPi− 2 and *VPi2 ≡ [VO2(picolinate)2]− are shown. The speciation diagram was kindly provided by A. Gorzsás, University of Umeå; see also ref. [12].



also the ionic strength) of the medium, up to six stable vanadate species of different degrees of nuclearity can be present; “normal” physiological conditions (pH ca. 7, cV b 1 μM) restrict the number of vanadate 2− species to monovanadate H2VO− . In the presence of phosphate 4 /HVO4 or peroxide, phospo- and peroxidovanadates are generated. Biogenic ligands such as dipeptides, nucleosides, imidazole, lactate and citrate interact with vanadate and peroxidovanadate to form oxido/ peroxidovanadium(V)–ligand complexes of varying composition, molecular structure, protonation state and stability. In view of the potentiality of vanadium compounds in the treatment of diseases, type II diabetes in particular, the pro-ligands picolinic acid and maltol had been included in these systematic investigations. The overall impact of the work of the Pettersson group has been potentiated and carried forth as a consequence of close cooperation initiated by Lage on the international level. Lage's obsession for details, for integrity and completeness, paired with his high scientific standard, and “modulated” by his psychosocial competence and humoristic attitude, have largely contributed to the scholarly output and impact of the many research findings that have conjunctly been acquired. References [1] L. Pettersson, B. Hedman, A.-M. Nenner, I. Andersson, Acta Chem. Scand. A39 (1985) 499–506. [2] L. Pettersson, I. Andersson, B. Hedman, Chem. Scr. 25 (1985) 309–317. [3] L. Pettersson, 25 (1971) 1959-1974. [4] L. Pettersson, I. Andersson, L. Lyhamn, N. Ingri, Kungliga Tekniska Högskolans Handlingar, 248-296, 1972, pp. 107–123. [5] M. Hashimoto, I. Andersson, L. Pettersson, J. Chem. Soc. Dalton Trans. (2007) 124–132. [6] M.-A. Saito, M. Hashimoto, Dalton Trans. 43 (2014) 402–405. [7] L. Pettersson, D.-G. Lyxell, I. Persson, Polyhedron 81 (2014) 308–311. [8] O.W. Howarth, L. Pettersson, I. Andersson, J. Chem. Soc. Dalton Trans. (1989) 1915–1923. [9] A. Selling, I. Andersson, J.H. Grate, L. Pettersson, Eur. J. Inorg. Chem. (2000) 1509–1521. [10] I. Andersson, J.J. Hastings, O.W. Howarth, L. Pettersson, J. Chem. Soc. Dalton Trans. (1996) 2705–2711.

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Interactions between natural organic matter and organic pollutants as revealed by NMR spectroscopy.

Acetone-induced polymerisation of 3-aminopropyltrimethoxysilane (APTMS) as revealed by NMR spectroscopy.

Acetone-induced polymerization of 3-aminopropyltrimethoxysilane (APTMS) as revealed by NMR spectroscopy – revisited.

Molecular dynamics of neutral polymer bonding agent (NPBA) as revealed by solid-state NMR spectroscopy.

1H and 51V NMR studies of the interaction of vanadate and 2-vanadio-3-phosphoglycerate with phosphoglycerate mutase.

Production of Citrate by Anaerobic Fungi in the Presence of Co-culture Methanogens as Revealed by (1)H NMR Spectrometry.

Just a Flexible Linker? The Structural and Dynamic Properties of CBP-ID4 Revealed by NMR Spectroscopy.

Global Dynamics and Exchange Kinetics of a Protein on the Surface of Nanoparticles Revealed by Relaxation-Based Solution NMR Spectroscopy.

Mechanisms of amyloid formation revealed by solution NMR.

Correlation of cofactor binding and the quaternary structure of pyruvate decarboxylase as revealed by 31P NMR spectroscopy.

Tapping the translation potential of cAMP signalling: molecular basis for selectivity in cAMP agonism and antagonism as revealed by NMR.