1q4v
From Proteopedia
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CRYSTAL STRUCTURE OF ALLO-ILEA2-INSULIN, AN INACTIVE CHIRAL ANALOGUE: IMPLICATIONS FOR THE MECHANISM OF RECEPTOR
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Overview
The crystal structure of an inactive chiral analogue of insulin containing, nonstandard substitution allo-Ile(A2) is described at 2.0 A resolution. In, native insulin, the invariant Ile(A2) side chain anchors the N-terminal, alpha-helix of the A-chain to the hydrophobic core. The structure of the, variant protein was determined by molecular replacement as a T(3)R(3) zinc, hexamer. Whereas respective T- and R-state main-chain structures are, similar to those of native insulin (main-chain root-mean-square deviations, (RMSD) of 0.45 and 0.54 A, respectively), differences in core packing are, observed near the variant side chain. The R-state core resembles that of, the native R-state with a local inversion of A2 orientation (core side, chain RMSD 0.75 A excluding A2); in the T-state, allo-Ile(A2) exhibits an, altered conformation in association with the reorganization of the, surrounding side chains (RMSD 0.98 A). Surprisingly, the core of the, R-state is similar to that observed in solution nuclear magnetic resonance, (NMR) studies of an engineered T-like monomer containing the same chiral, substitution (allo-Ile(A2)-DKP-insulin; Xu, B., Hua, Q. X., Nakagawa, S., H., Jia, W., Chu, Y. C., Katsoyannis, P. G., and Weiss, M. A. (2002) J., Mol. Biol. 316, 435-441). Simulation of NOESY spectra based on, crystallographic protomers enables the analysis of similarities and, differences in solution. The different responses of the T- and R-state, cores to chiral perturbation illustrates both their intrinsic plasticity, and constraints imposed by hexamer assembly. Although variant T- and, R-protomers retain nativelike protein surfaces, the receptor-binding, activity of allo-Ile(A2)-insulin is low (2% relative to native insulin)., This seeming paradox suggests that insulin undergoes a change in, conformation to expose Ile(A2) at the hormone-receptor interface.
Disease
Known diseases associated with this structure: Diabetes mellitus, rare form OMIM:[176730], Hyperproinsulinemia, familial OMIM:[176730], MODY, one form OMIM:[176730]
About this Structure
1Q4V is a Single protein structure of sequence from [1] with ZN and IPH as ligands. This structure superseeds the now removed PDB entries 1PC1 and 1LW8. Full crystallographic information is available from OCA.
Reference
Crystal structure of allo-Ile(A2)-insulin, an inactive chiral analogue: implications for the mechanism of receptor binding., Wan ZL, Xu B, Chu YC, Katsoyannis PG, Weiss MA, Biochemistry. 2003 Nov 11;42(44):12770-83. PMID:14596591
Page seeded by OCA on Mon Nov 12 18:50:32 2007
