1HIT

Receptor binding redefined by a structural switch in a mutant Human Insulin

1HIT の概要

• エントリーDOI: 10.2210/pdb1hit/pdb
• 分子名称: INSULIN (2 entities in total)
• 機能のキーワード: hormone
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 5727.53

構造登録者

Hua, Q.X.,Kochoyan, M.,Weiss, M.A. (登録日: 1992-02-28, 公開日: 1994-01-31, 最終更新日: 2024-10-30)

主引用文献

Hua, Q.X.,Shoelson, S.E.,Kochoyan, M.,Weiss, M.A.
Receptor binding redefined by a structural switch in a mutant human insulin.
Nature, 354:238-241, 1991

PubMed 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.

PubMed: 1961250
DOI: 10.1038/354238a0

実験手法

SOLUTION NMR