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TitlePlatelet integrin αIIbβ3 plays a key role in a venous thrombogenesis mouse model.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 8612, Year 2024
Publish dateOct 4, 2024
AuthorsBrian D Adair / Conroy O Field / José L Alonso / Jian-Ping Xiong / Shi-Xian Deng / Hyun Sook Ahn / Eivgeni Mashin / Clary B Clish / Johannes van Agthoven / Mark Yeager / Youzhong Guo / David A Tess / Donald W Landry / Mortimer Poncz / M Amin Arnaout /
PubMed AbstractVenous 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 ...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.
External linksNat Commun / PubMed:39366965 / PubMed Central
MethodsEM (single particle)
Resolution3.9 - 4.1 Å
Structure data

46793

9deq

EMDB-46793, PDB-9deq:
Cryo-EM structures of full-length integrin alphaIIbbeta3 in native lipids complexed with modified tirofiban
Method: EM (single particle) / Resolution: 4.1 Å

46794

9der

EMDB-46794, PDB-9der:
Cryo-EM Structures of Full-Length Integrin alphaIIbbeta3 in Native Lipids Complexed with Tirofiban
Method: EM (single particle) / Resolution: 3.9 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-MG:
Unknown entry

PDB-1a5g:
HUMAN THROMBIN COMPLEXED WITH NOVEL SYNTHETIC PEPTIDE MIMETIC INHIBITOR AND HIRUGEN

ChemComp-CLR:
CHOLESTEROL

ChemComp-HOH:
WATER

ChemComp-AGG:
TIROFIBAN / medication, inhibitor*YM

Source
  • homo sapiens (human)
KeywordsCELL ADHESION / complex / open headpiece

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