1hit

From Proteopedia

Revision as of 09:37, 20 March 2008

RECEPTOR BINDING REDEFINED BY A STRUCTURAL SWITCH IN A MUTANT HUMAN INSULIN

Overview

Crystal structures of insulin have been determined in various distinct forms, the relevance of which to receptor recognition has long been the subject of speculation. Recently the crystal structure of an inactive insulin analogue has been determined and, surprisingly, found to have a conformation identical to native insulin. On this basis Dodson and colleagues have suggested that the known insulin crystal structures reflect an inactive conformation, and that a change in conformation is required for activity--specifically, the carboxy terminal residues of the B-chain are proposed to separate from the amino terminal residues of the A-chain. Here we report the solution structure of an active insulin mutant, determined by two-dimensional NMR, which supports this hypothesis. In the mutant, the carboxy terminal beta-turn and beta-strand of the B-chain are destabilized and do not pack across the rest of the molecule. We suggest that analogous detachment of the carboxy terminal region of the B-chain occurs in native insulin on binding to its receptor. Our finding that partial unfolding of the B-chain exposes an alternative protein surface rationalizes the receptor-binding properties of a series of anomalous insulin analogues, including a mutant insulin associated with diabetes mellitus in man.

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

1HIT is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Receptor binding redefined by a structural switch in a mutant human insulin., Hua QX, Shoelson SE, Kochoyan M, Weiss MA, Nature. 1991 Nov 21;354(6350):238-41. PMID:1961250

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