Rhombohedral insulin crystal transformation

Bentley, G.A.; Dodson, Guy; Lewitova, Anita

doi:10.1016/0022-2836(78)90026-8

Cited by 42 publications

(40 citation statements)

References 4 publications

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confidence: 99%

“…DPI retains sufficient structural information for proper function and folding (4)(5)(6)(7)(8)(9)(10)(11)(12)(13), and its crystal structure is similar to the corresponding portion ofthe intact protein (6,7). Crystal structures of DPI and native insulin have been determined in a variety of forms (6)(7)(8)(9)(10)(11). Individual protomers exhibit distinctive features, which may be classified as local and uncorrelated (alternative configurations of surface side chains), transitions in secondary structure (the N-terminal a-helical extension of the B-chain a-helix in the phenol-related hexamer), and nonlocal and correlated (rigid-body displacement of elements of secondary structure).…”

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Structure and dynamics of des-pentapeptide-insulin in solution: the molten-globule hypothesis.

Hua

Kochoyan

Weiss

1992

Proc. Natl. Acad. Sci. U.S.A.

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Structures of insulin in different crystal forms exhibit significant local and nonlocal differences, including correlated displacement of elements of secondary structure. Here we describe the solution structure and dynamics of a monomeric insulin analogue, des-pentapeptide-(B26-B30)-insulin (DPI), as determined by two-dimensional NMR spectroscopy and distance geometry/restrained molecular dynamics (DG/RMD). Although the solution structure of DPI exhibits a general similarity to its crystal structure, individual DG/RMD structures in the NMR ensemble differ by rigid-body displacements of alpha-helices that span the range of different crystal forms. These results suggest that DPI exists as a partially folded state formed by coalescence of distinct alpha-helix-associated microdomains. The physical reality of this model is investigated by comparison of the observed two-dimensional nuclear Overhauser enhancement (NOE) spectroscopy (NOESY) spectrum with that predicted from crystal and DG/RMD structures. The observed NOESY spectrum contains fewer tertiary contacts than predicted by any single simulation, but it matches their shared features; such "ensemble correspondence" is likely to reflect the effect of protein dynamics on observed NOE intensities. We propose (i) that the folded state of DPI is analogous to that of a compact protein-folding intermediate rather than a conventional native state and (ii) that the molten state is the biologically active species. This proposal (the molten-globule hypothesis) leads to testable thermodynamic predictions and has general implications for protein design.

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confidence: 99%

Structure and dynamics of des-pentapeptide-insulin in solution: the molten-globule hypothesis.

Hua

Kochoyan

Weiss

1992

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition to changes in humidity, changes in ionic strength or the pH of the medium are also known to cause structural transformations in protein crystals. Extensive conformational changes are known to occur in the transformation of 2Zn to 4Zn insulin caused by a change in ionic strength (Bentley, Dodson & Lewitova, 1978). Similarly, the molecular structure of adenylate kinase changes substantially during the transformation of its crystals mediated by a change in pH (Sachsenheimer & Schulz, 1977).…”

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Water-mediated transformations in protein crystals

Salunke¹,

Veerapandian²,

Kodandapani³

et al. 1985

Acta Crystallogr Sect B

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Different crystal forms of bovine pancreatic ribonuclease A and hen egg white lysozyme, 2Zn insulin, 4Zn insulin and crystals of concanavalin A were examined under controlled environmental humidity in the relative humidity (r.h.) range of 100 to 75%. Many of them, but not all, undergo reversible structural transformations as evidenced by discontinuous changes in the diffraction pattern, the unit-cell dimensions and the solvent content. Tetragonal, orthorhombic and monoclinic lysozyme and a new crystal form of ribonuclease A show transformations at r.h.'s above 90%. Monoclinic lysozyme transforms at low r.h. to another monoclinic form with nearly half the original cell volume. The well known monoclinic form of ribonuclease A grown from aqueous ethanol solution undergoes two transformations while the same form grown from 2-methyl-2,4-pentanediol (MPD) solution in phosphate buffer does not transform at all. Soaking experiments involving alcohol solutions demonstrate that MPD has the effect of decreasing the r.h. at which the transformation occurs. Triclinic lysozyme, 2Zn insulin, 4Zn insulin and the crystals of cancanavalin A do not transform in the 100 to 75% r.h. range before losing crystallinity. The results obtained so far indicate that the crystal structure has a definite influence on water-mediated transformations. The transformations do not appear to depend critically on the amount of solvent in the crystals but the r.h. at which they occur is influenced by the composition of the solvent. The transformations appear to involve changes in crystal packing as well as conformational transitions in protein molecules. The present investigations and other related studies suggest that water-mediated transformations in protein crystals could be very useful in 0108-7681/85/060431-06501.50 exploring conformational transitions in and the hydration of proteins.

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“…For instance, the porcine 4-Zn insulin structure has an additional helical region running from B1 to B8 [4], whereas in 2-Zn insulin this fragment is in a random coil conformation. In fact, a variety of solution and crystal studies showed that the conversion of the 2-Zn to the 4-Zn structure can be induced by high concentrations of anions [7]. Adding…”

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The solution structure of a monomeric insulin

Knegtel

Boelens

Ganadu

et al. 1991

European Journal of Biochemistry

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The solution conformation of des-(B26-B30)-insulin (DPI) has been investigated by 'H-NMR spectroscopy. A set of 250 approximate interproton distance restraints, derived from two-dimensional nuclear Overhauser enhancement spectra, were used as the basis of a structure determination using distance geometry (DG) and distance-bound driven dynamics (DDD). Sixteen DG structures were optimized using energy minimization (EM) and submitted to short 5-ps restrained molecular dynamics (RMD) simulations. A further refinement of the DDD structure with the lowest distance errors was done by energy minimization, a prolonged RMD simulation in VUL'UO and a time-averaged RMD simulation. An average structure was obtained from a trajectory generated during 20-ps RMD. The final structure was compared with the des-(B26 -B30)-insulin crystal structure refined by molecular dynamics and the 2-Zn crystal structure of porcine insulin. This comparison shows that the overall structure of des-(B26 -B30)-insulin is retained in solution with respect to the crystal structures with a high flexibility at the N-terminal part of the A chain and at the N-terminal and C-terminal parts of the B chain. In the RMD run a high mobility of Gly A l , Asn A21 and of the side chain of Phe B25 is noticed. One of the conformations adopted by des-(B26-B30)-insulin in solution is similar to that of molecule 1 (Chinese nomenclature) in the crystal structure of porcine insulin.Due to its biological importance as a hormone and drug, insulin has been the subject of numerous studies regarding its structure and function [l]. Several crystal structures of insulins have been reported [2 -61 and a detailed picture of the spatial structure of insulins has emerged.The insulin molecule consists of two polypeptide chains, A and B, of 21 and 30 residues respectively (cf. Fig. 1). The horse-shoe-shaped A chain contains two helices (residues A2-A8 and A13-A20) and the B chain one helix (residues B9 -BI 9). These chains are connected by two disulphide bridges (A7 -B7 and A20 -B19) which, together with a third one (A6 -A1 I), help stabilize the folded form of insulin over a broad range of temperatures and pH values. In the crystal structures the last six residues of the B chain form an antiparallel fl-sheet with another insulin molecule. Insulin is a rather flexible molecule, as evidenced by large structural differences found in different crystal structures. The major differences between various forms of insulin are in the N-terminal of the B chain. For instance, the porcine 4-Zn insulin structure has an additional helical region running from B1 to B8 [4], whereas in 2-Zn insulin this fragment is in a random coil conformation. In fact, a variety of solution and crystal studies showed that the conversion of the 2-Zn to the 4-Zn structure can be induced by high concentrations of anions [7]. Adding Correspondence to R . Boelens, Department of Chemistry, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The NetherlandsAhbveviutions. Des-(3326 -B30)-insulin, insulin lacking the C-te...

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Rhombohedral insulin crystal transformation

Cited by 42 publications

References 4 publications

Structure and dynamics of des-pentapeptide-insulin in solution: the molten-globule hypothesis.

Structure and dynamics of des-pentapeptide-insulin in solution: the molten-globule hypothesis.

Water-mediated transformations in protein crystals

The solution structure of a monomeric insulin

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