1vkt

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HUMAN INSULIN TWO DISULFIDE MODEL, NMR, 10 STRUCTURES

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

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

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