1xw7
From Proteopedia
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[[Image:1xw7.gif|left|200px]] | [[Image:1xw7.gif|left|200px]] | ||
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'''Diabetes-Associated Mutations in Human Insulin: Crystal Structure and Photo-Cross-Linking Studies of A-Chain Variant Insulin Wakayama''' | '''Diabetes-Associated Mutations in Human Insulin: Crystal Structure and Photo-Cross-Linking Studies of A-Chain Variant Insulin Wakayama''' | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1XW7 is a [[Protein complex]] structure | + | 1XW7 is a [[Protein complex]] structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XW7 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Weiss, M A.]] | [[Category: Weiss, M A.]] | ||
[[Category: Xu, B.]] | [[Category: Xu, B.]] | ||
| - | [[Category: | + | [[Category: Insulin receptor]] |
| - | [[Category: | + | [[Category: Leu-a30insulin]] |
| - | [[Category: | + | [[Category: Protein unfolding]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 15:34:57 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 12:34, 3 May 2008
Diabetes-Associated Mutations in Human Insulin: Crystal Structure and Photo-Cross-Linking Studies of A-Chain Variant Insulin Wakayama
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.
About this Structure
1XW7 is a Protein complex structure. 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 Page seeded by OCA on Sat May 3 15:34:57 2008
