1xw7

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{{STRUCTURE_1xw7| PDB=1xw7 | SCENE= }}
{{STRUCTURE_1xw7| PDB=1xw7 | SCENE= }}
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'''Diabetes-Associated Mutations in Human Insulin: Crystal Structure and Photo-Cross-Linking Studies of A-Chain Variant Insulin Wakayama'''
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===Diabetes-Associated Mutations in Human Insulin: Crystal Structure and Photo-Cross-Linking Studies of A-Chain Variant Insulin Wakayama===
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==Overview==
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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.
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{{ABSTRACT_PUBMED_15794638}}
==About this Structure==
==About this Structure==
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==Reference==
==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:[http://www.ncbi.nlm.nih.gov/pubmed/15794638 15794638]
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:[http://www.ncbi.nlm.nih.gov/pubmed/15794638 15794638]
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Crystallographic titration of cubic insulin crystals: pH affects GluB13 switching and sulfate binding., Diao J, Acta Crystallogr D Biol Crystallogr. 2003 Apr;59(Pt 4):670-6. Epub 2003, Mar 25. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/12657786 12657786]
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Structure of cubic insulin crystals in glucose solutions., Yu B, Caspar DL, Biophys J. 1998 Jan;74(1):616-22. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9449362 9449362]
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Structure of the pig insulin dimer in the cubic crystal., Badger J, Harris MR, Reynolds CD, Evans AC, Dodson EJ, Dodson GG, North AC, Acta Crystallogr B. 1991 Feb 1;47 ( Pt 1):127-36. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/2025410 2025410]
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Water structure in cubic insulin crystals., Badger J, Caspar DL, Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):622-6. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/1988957 1988957]
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Zinc-free cubic pig insulin: crystallization and structure determination., Dodson EJ, Dodson GG, Lewitova A, Sabesan M, J Mol Biol. 1978 Nov 5;125(3):387-96. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/731699 731699]
[[Category: Protein complex]]
[[Category: Protein complex]]
[[Category: Chu, Y C.]]
[[Category: Chu, Y C.]]
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[[Category: Leu-a30insulin]]
[[Category: Leu-a30insulin]]
[[Category: Protein unfolding]]
[[Category: Protein unfolding]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 14:22:25 2008''

Revision as of 11:22, 28 July 2008

Image:1xw7.png

Template:STRUCTURE 1xw7

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

Template:ABSTRACT PUBMED 15794638

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

Crystallographic titration of cubic insulin crystals: pH affects GluB13 switching and sulfate binding., Diao J, Acta Crystallogr D Biol Crystallogr. 2003 Apr;59(Pt 4):670-6. Epub 2003, Mar 25. PMID:12657786

Structure of cubic insulin crystals in glucose solutions., Yu B, Caspar DL, Biophys J. 1998 Jan;74(1):616-22. PMID:9449362

Structure of the pig insulin dimer in the cubic crystal., Badger J, Harris MR, Reynolds CD, Evans AC, Dodson EJ, Dodson GG, North AC, Acta Crystallogr B. 1991 Feb 1;47 ( Pt 1):127-36. PMID:2025410

Water structure in cubic insulin crystals., Badger J, Caspar DL, Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):622-6. PMID:1988957

Zinc-free cubic pig insulin: crystallization and structure determination., Dodson EJ, Dodson GG, Lewitova A, Sabesan M, J Mol Biol. 1978 Nov 5;125(3):387-96. PMID:731699

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