9DER

Cryo-EM Structures of Full-Length Integrin alphaIIbbeta3 in Native Lipids Complexed with Tirofiban

9DER の概要

• エントリーDOI: 10.2210/pdb9der/pdb
• EMDBエントリー: 46794
• 分子名称: Integrin alpha-IIb, Integrin beta-3, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• 機能のキーワード: complex, open headpiece, cell adhesion
• 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: 198385.11

構造登録者

Adair, B.,Xiong, J.P.,Yeager, M.,Arnaout, M.A. (登録日: 2024-08-29, 公開日: 2024-10-16, 最終更新日: 2024-11-13)

主引用文献

Adair, B.D.,Field, C.O.,Alonso, J.L.,Xiong, J.P.,Deng, S.X.,Ahn, H.S.,Mashin, E.,Clish, C.B.,van Agthoven, J.,Yeager, M.,Guo, Y.,Tess, D.A.,Landry, D.W.,Poncz, M.,Arnaout, M.A.
Platelet integrin alpha IIb beta 3 plays a key role in a venous thrombogenesis mouse model.
Nat Commun, 15:8612-8612, 2024

PubMed Abstract: Venous thrombosis (VT) is a common vascular disease associated with reduced survival and a high recurrence rate. VT is initiated by the accumulation of platelets and neutrophils at sites of endothelial cell activation. A role for platelet αIIbβ3 in VT is not established, a task complicated by the increased bleeding risk caused by partial agonists such as tirofiban. Here, we show that m-tirofiban, a modified version of tirofiban, does not agonize αIIbβ3 based on lack of neoepitope expression and the cryo-EM structure of m-tirofiban/full-length αIIbβ3 complex. m-tirofiban abolishes agonist-induced platelet aggregation while preserving clot retraction ex vivo and, unlike tirofiban, it suppresses venous thrombogenesis in a mouse model without increasing bleeding. These findings establish a key role for αIIbβ3 in VT initiation and suggest that m-tirofiban and compounds with a similar structurally-defined mechanism of action merit consideration as potential thromboprophylaxis agents in patients at high risk for VT and hemorrhage.

PubMed: 39366965
DOI: 10.1038/s41467-024-52869-3

実験手法

ELECTRON MICROSCOPY (3.9 Å)