1KMF

NMR STRUCTURE OF HUMAN INSULIN MUTANT ILE-A2-ALLO-ILE, HIS-B10-ASP, PRO-B28-LYS, LYS-B29-PRO, 15 STRUCTURES

1KMF の概要

• エントリーDOI: 10.2210/pdb1kmf/pdb
• 関連するPDBエントリー: 1K3M
• NMR情報: BMRB: 5246
• 分子名称: Insulin (2 entities in total)
• 機能のキーワード: hormone, human insulin, mutant, hormone-growth factor complex, hormone/growth factor
• 細胞内の位置: Secreted: P01308 P01308
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 5794.59

構造登録者

Xu, B.,Hua, Q.X.,Nakagawa, S.H.,Jia, W.,Chu, Y.C.,Katsoyannis, P.G.,Weiss, M.A. (登録日: 2001-12-14, 公開日: 2002-01-09, 最終更新日: 2024-11-06)

主引用文献

Xu, B.,Hua, Q.X.,Nakagawa, S.H.,Jia, W.,Chu, Y.C.,Katsoyannis, P.G.,Weiss, M.A.
Chiral mutagenesis of insulin's hidden receptor-binding surface: structure of an allo-isoleucine(A2) analogue.
J.Mol.Biol., 316:435-441, 2002

PubMed Abstract: The hydrophobic core of vertebrate insulins contains an invariant isoleucine residue at position A2. Lack of variation may reflect this side-chain's dual contribution to structure and function: Ile(A2) is proposed both to stabilize the A1-A8 alpha-helix and to contribute to a "hidden" functional surface exposed on receptor binding. Substitution of Ile(A2) by alanine results in segmental unfolding of the A1-A8 alpha-helix, lower thermodynamic stability and impaired receptor binding. Such a spectrum of perturbations, although of biophysical interest, confounds interpretation of structure-activity relationships. To investigate the specific contribution of Ile(A2) to insulin's functional surface, we have employed non-standard mutagenesis: inversion of side-chain chirality in engineered monomer allo-Ile(A2)-DKP-insulin. Although the analogue retains native structure and stability, its affinity for the insulin receptor is impaired by 50-fold. Thus, whereas insulin's core readily accommodates allo-isoleucine at A2, its activity is exquisitely sensitive to chiral inversion. We propose that the Ile(A2) side-chain inserts within a chiral pocket of the receptor as part of insulin's hidden functional surface.

PubMed: 11866509
DOI: 10.1006/jmbi.2001.5377

実験手法

SOLUTION NMR