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Receptor binding redefined by a structural switch in a mutant human insulin.

Abstract：

: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.

journal_name

Nature

journal_title

Nature

authors

Hua QX,Shoelson SE,Kochoyan M,Weiss MA

doi

10.1038/354238a0

subject

Has Abstract

pub_date

1991-11-21 00:00:00

pages

238-41

issue

6350

eissn

0028-0836

issn

1476-4687

journal_volume

354

pub_type

杂志文章

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