1vkt
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Functional surfaces of a protein are often mapped by combination of X-ray | + | Functional surfaces of a protein are often mapped by combination of X-ray crystallography and mutagenesis. Such studies of insulin have yielded paradoxical results, suggesting that the native state is inactive and reorganizes on receptor binding. Of particular interest is the N-terminal alpha-helix of the A-chain. Does this segment function as an alpha-helix or reorganize as recently proposed in a prohormone-convertase complex? To correlate structure and function, we describe a mapping strategy based on protein design. The solution structure of an engineered monomer ([AspB10, LysB28, ProB29]-human insulin) is determined at neutral pH as a template for synthesis of a novel A-chain analogue. Designed by analogy to a protein-folding intermediate, the analogue lacks the A6-A11 disulphide bridge; the cysteine residues are replaced by serine. Its solution structure is remarkable for segmental unfolding of the N-terminal A-chain alpha-helix (A1 to A8) in an otherwise native subdomain. The structure demonstrates that the overall orientation of the A and B chains is consistent with reorganization of the A-chain's N-terminal segment. Nevertheless, the analogue's low biological activity suggests that this segment, a site of clinical mutation causing diabetes mellitus, functions as a preformed recognition alpha-helix. |
==Disease== | ==Disease== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Burke, G | + | [[Category: Burke, G T.]] |
| - | [[Category: Chu, Y | + | [[Category: Chu, Y C.]] |
| - | [[Category: Frank, B | + | [[Category: Frank, B H.]] |
| - | [[Category: Hu, S | + | [[Category: Hu, S Q.]] |
| - | [[Category: Hua, Q | + | [[Category: Hua, Q X.]] |
| - | [[Category: Jia, W | + | [[Category: Jia, W H.]] |
| - | [[Category: Katsoyannis, P | + | [[Category: Katsoyannis, P G.]] |
| - | [[Category: Wang, S | + | [[Category: Wang, S H.]] |
| - | [[Category: Weiss, M | + | [[Category: Weiss, M A.]] |
[[Category: disulfide model]] | [[Category: disulfide model]] | ||
[[Category: hormone]] | [[Category: hormone]] | ||
[[Category: human insulin]] | [[Category: human insulin]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:36:22 2008'' |
Revision as of 13:36, 21 February 2008
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HUMAN INSULIN TWO DISULFIDE MODEL, NMR, 10 STRUCTURES
Contents |
Overview
Functional surfaces of a protein are often mapped by combination of X-ray crystallography and mutagenesis. Such studies of insulin have yielded paradoxical results, suggesting that the native state is inactive and reorganizes on receptor binding. Of particular interest is the N-terminal alpha-helix of the A-chain. Does this segment function as an alpha-helix or reorganize as recently proposed in a prohormone-convertase complex? To correlate structure and function, we describe a mapping strategy based on protein design. The solution structure of an engineered monomer ([AspB10, LysB28, ProB29]-human insulin) is determined at neutral pH as a template for synthesis of a novel A-chain analogue. Designed by analogy to a protein-folding intermediate, the analogue lacks the A6-A11 disulphide bridge; the cysteine residues are replaced by serine. Its solution structure is remarkable for segmental unfolding of the N-terminal A-chain alpha-helix (A1 to A8) in an otherwise native subdomain. The structure demonstrates that the overall orientation of the A and B chains is consistent with reorganization of the A-chain's N-terminal segment. Nevertheless, the analogue's low biological activity suggests that this segment, a site of clinical mutation causing diabetes mellitus, functions as a preformed recognition alpha-helix.
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
1VKT is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Mapping the functional surface of insulin by design: structure and function of a novel A-chain analogue., Hua QX, Hu SQ, Frank BH, Jia W, Chu YC, Wang SH, Burke GT, Katsoyannis PG, Weiss MA, J Mol Biol. 1996 Nov 29;264(2):390-403. PMID:8951384
Page seeded by OCA on Thu Feb 21 15:36:22 2008
