1xw7

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spinqualitylabelsall models 1xw7, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Diabetes-Associated Mutations in Human Insulin: Crystal Structure and Photo-Cross-Linking Studies of A-Chain Variant Insulin Wakayama

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Naturally occurring mutations in insulin associated with diabetes mellitus, identify critical determinants of its biological activity. Here, we, describe the crystal structure of insulin Wakayama, a clinical variant in, which a conserved valine in the A chain (residue A3) is substituted by, leucine. The substitution occurs within a crevice adjoining the classical, receptor-binding surface and impairs receptor binding by 500-fold, an, unusually severe decrement among mutant insulins. To resolve whether such, decreased activity is directly or indirectly mediated by the variant side, chain, we have determined the crystal structure of Leu(A3)-insulin and, investigated the photo-cross-linking properties of an A3 analogue, containing p-azidophenylalanine. The structure, characterized in a novel, crystal form as an R(6) zinc hexamer at 2.3 A resolution, is essentially, identical to that of the wild-type R(6) hexamer. The variant side chain, remains buried in a nativelike crevice with small adjustments in, surrounding side chains. The corresponding photoactivatable analogue, although of low affinity, exhibits efficient cross-linking to the insulin, receptor. The site of photo-cross-linking lies within a 14 kDa C-terminal, domain of the alpha-subunit. This domain, unrelated in sequence to the, major insulin-binding region in the N-terminal L1 beta-helix, is also, contacted by photoactivatable probes at positions A8 and B25. Packing of, Val(A3) at this interface may require a conformational change in the B, chain to expose the A3-related crevice. The structure of insulin Wakayama, thus evokes the reasoning of Sherlock Holmes in "the curious incident of, the dog in the night": the apparent absence of structural perturbations, (like the dog that did not bark) provides a critical clue to the function, of a hidden receptor-binding surface.

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

1XW7 is a Protein complex structure of sequences from [1] with ZN, CL and IPH as ligands. Full crystallographic information is available from OCA.

Reference

Diabetes-associated mutations in human insulin: crystal structure and photo-cross-linking studies of a-chain variant insulin Wakayama., Wan ZL, Huang K, Xu B, Hu SQ, Wang S, Chu YC, Katsoyannis PG, Weiss MA, Biochemistry. 2005 Apr 5;44(13):5000-16. PMID:15794638

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