9DEQ

Cryo-EM structures of full-length integrin alphaIIbbeta3 in native lipids complexed with modified tirofiban

This is a non-PDB format compatible entry.

Summary for 9DEQ

• Entry DOI: 10.2210/pdb9deq/pdb
• EMDB information: 46793
• Descriptor: Integrin alpha-IIb, CHOLESTEROL, Integrin beta-3, ... (11 entities in total)
• Functional Keywords: complex, open headpiece, cell adhesion
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 200753.88

Authors

Adair, B.,Xiong, J.P.,Yeager, M.,Arnaout, M.A. (deposition date: 2024-08-29, release date: 2024-10-16, Last modification date: 2024-10-30)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (4.1 Å)