1ZEG

STRUCTURE OF B28 ASP INSULIN IN COMPLEX WITH PHENOL

1ZEG の概要

• エントリーDOI: 10.2210/pdb1zeg/pdb
• 分子名称: INSULIN, PHENOL, ZINC ION, ... (6 entities in total)
• 機能のキーワード: hormone, metabolic role, chemical activity, insulin mutant, cross-link, glucose metabolism, diabetes
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Secreted: P01308 P01308
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 12155.31

構造登録者

Whittingham, J.L.,Edwards, E.J.,Antson, A.A.,Clarkson, J.M.,Dodson, G.G. (登録日: 1998-05-01, 公開日: 1998-07-15, 最終更新日: 2024-10-16)

主引用文献

Whittingham, J.L.,Edwards, D.J.,Antson, A.A.,Clarkson, J.M.,Dodson, G.G.
Interactions of phenol and m-cresol in the insulin hexamer, and their effect on the association properties of B28 pro --> Asp insulin analogues.
Biochemistry, 37:11516-11523, 1998

PubMed Abstract: Insulin's natural tendency to form dimers and hexamers is significantly reduced in a mutant insulin B28 Pro --> Asp, which has been designed as a monomeric, rapid-acting hormone for therapeutic purposes. This molecule can be induced to form zinc hexamers in the presence of small phenolic derivatives which are routinely used as antimicrobial agents in insulin preparations. Two structures of B28 Asp insulin have been determined from crystals grown in the presence of phenol and m-cresol. In these crystals, insulin exists as R6 zinc hexamers containing a number of phenol or m-cresol molecules associated with aromatic side chains at the dimer-dimer interfaces. At the monomer-monomer interfaces, the B28 Pro --> Asp mutation leads to increased conformational flexibility in the B chain C termini, resulting in the loss of important intermolecular van der Waals contacts, thus explaining the monomeric character of B28 Asp insulin. The structure of a cross-linked derivative of B28 Asp insulin, containing an Ala-Lys dipeptide linker between residues B30 Ala and A1 Gly, has also determined. This forms an R6 zinc hexamer containing several m-cresol molecules. Of particular interest in this structure are two m-cresol molecules whose binding disrupted the beta-strand in one of the dimers. This observation suggests that the cross-link introduces mechanical strain on the B chain C terminus, thereby weakening the monomer-monomer interactions.

PubMed: 9708987
DOI: 10.1021/bi980807s

実験手法

X-RAY DIFFRACTION (1.6 Å)