5BQQ

Human insulin with intra-chain chemical crosslink between modified B27 and B30

5BQQ の概要

• エントリーDOI: 10.2210/pdb5bqq/pdb
• 分子名称: Insulin, PHENOL, ZINC ION, ... (6 entities in total)
• 機能のキーワード: chemical crosslink, b24-b29, specificity, hormone
• 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: 12
• 化学式量合計: 35826.28

構造登録者

Brzozowski, A.M.,Turkenburg, J.P.,Jiracek, J.,Zakova, L. (登録日: 2015-05-29, 公開日: 2016-02-03, 最終更新日: 2025-10-01)

主引用文献

Vikova, J.,Collinsova, M.,Kletvikova, E.,Budesinsky, M.,Kaplan, V.,Zakova, L.,Veverka, V.,Hexnerova, R.,Avino, R.J.,Strakova, J.,Selicharova, I.,Vanek, V.,Wright, D.W.,Watson, C.J.,Turkenburg, J.P.,Brzozowski, A.M.,Jiracek, J.
Rational steering of insulin binding specificity by intra-chain chemical crosslinking.
Sci Rep, 6:19431-19431, 2016

PubMed Abstract: Insulin is a key hormone of human metabolism with major therapeutic importance for both types of diabetes. New insulin analogues with more physiological profiles and better glycemic control are needed, especially analogues that preferentially bind to the metabolic B-isoform of insulin receptor (IR-B). Here, we aimed to stabilize and modulate the receptor-compatible conformation of insulin by covalent intra-chain crosslinking within its B22-B30 segment, using the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of azides and alkynes. This approach resulted in 14 new, systematically crosslinked insulin analogues whose structures and functions were extensively characterized and correlated. One of the analogues, containing a B26-B29 triazole bridge, was highly active in binding to both IR isoforms, with a significant preference for IR-B. Our results demonstrate the potential of chemistry-driven modulation of insulin function, also shedding new light on the functional importance of hormone's B-chain C-terminus for its IR-B specificity.

PubMed: 26792393
DOI: 10.1038/srep19431

実験手法

X-RAY DIFFRACTION (1.54 Å)