Multiple discontinuous ligand-mimetic antibody binding sites define a ligand binding pocket in integrin α(IIb)β3

Wilma Puzon-McLaughlin, Tetsuji Kamata, Yoshikazu Takada

研究成果: 雜誌貢獻文章

87 引文 斯高帕斯(Scopus)

摘要

Integrin α(IIb)β3, a platelet fibrinogen receptor, is critically involved in thrombosis and hemostasis. However, how ligands interact with α(IIb)β3 has been controversial. Ligand-mimetic anti-α(IIb)β3 antibodies (PAC-1, LJ-CP3, and OP-G2) contain the RGD-like RYD sequence in their CDR3 in the heavy chain and have structural and functional similarities to native ligands. We have located binding sites for ligand-mimetic antibodies in α(IIb) and β3 using human-to-mouse chimeras, which we expect to maintain functional integrity of α(IIb)β3. Here we report that these antibodies recognize several discontinuous binding sites in both the α(IIb) and β3 subunits; these binding sites are located in residues 156-162 and 229230 of α(IIb) and residues 179-183 of β3. In contrast, several nonligand-mimetic antibodies (e.g. 7E3) recognize single epitopes in either subunit. Thus, binding to several discontinuous sites in both subunits is unique to ligand-mimetic antibodies. Interestingly, these binding sites overlap with several (but not all) of the sequences that have been reported to be critical for fibrinogen binding (e.g. N-terminal repeats 2-3 but not repeats 4-7, of a(IIb)). These results suggest that ligand-mimetic antibodies and probably native ligands may make direct contact with these discontinuous binding sites in both subunits, which may constitute a ligand-binding pocket.

原文英語
頁(從 - 到)7795-7802
頁數8
期刊Journal of Biological Chemistry
275
發行號11
DOIs
出版狀態已發佈 - 三月 17 2000
對外發佈Yes

ASJC Scopus subject areas

  • Biochemistry

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