7UKO

Integrin alpha IIB beta3 complex with sibrafiban (Mn)

7UKO の概要

• エントリーDOI: 10.2210/pdb7uko/pdb
• 関連するPDBエントリー: 7L8P 7UDG 7UE0 7UFH 7UH8 7UJK 7UK9
• 分子名称: Integrin alpha-IIb heavy chain, GLYCEROL, MANGANESE (II) ION, ... (15 entities in total)
• 機能のキーワード: complex, inhibitor, blood clotting, cell adhesion, cell adhesion-inhibitor complex, cell adhesion/inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 302459.80

構造登録者

Lin, F.-Y.,Zhu, J.,Zhu, J.,Springer, T.A. (登録日: 2022-04-01, 公開日: 2022-08-17, 最終更新日: 2024-10-16)

主引用文献

Lin, F.Y.,Li, J.,Xie, Y.,Zhu, J.,Huong Nguyen, T.T.,Zhang, Y.,Zhu, J.,Springer, T.A.
A general chemical principle for creating closure-stabilizing integrin inhibitors.
Cell, 185:3533-3550.e27, 2022

PubMed Abstract: Integrins are validated drug targets with six approved therapeutics. However, small-molecule inhibitors to three integrins failed in late-stage clinical trials for chronic indications. Such unfavorable outcomes may in part be caused by partial agonism, i.e., the stabilization of the high-affinity, extended-open integrin conformation. Here, we show that the failed, small-molecule inhibitors of integrins αIIbβ3 and α4β1 stabilize the high-affinity conformation. Furthermore, we discovered a simple chemical feature present in multiple αIIbβ3 antagonists that stabilizes integrins in their bent-closed conformation. Closing inhibitors contain a polar nitrogen atom that stabilizes, via hydrogen bonds, a water molecule that intervenes between a serine residue and the metal in the metal-ion-dependent adhesion site (MIDAS). Expulsion of this water is a requisite for transition to the open conformation. This change in metal coordination is general to integrins, suggesting broad applicability of the drug-design principle to the integrin family, as validated with a distantly related integrin, α4β1.

PubMed: 36113427
DOI: 10.1016/j.cell.2022.08.008

実験手法

X-RAY DIFFRACTION (2.604 Å)