7LA4
Integrin AlphaIIbBeta3-PT25-2 Complex
Summary for 7LA4
| Entry DOI | 10.2210/pdb7la4/pdb |
| EMDB information | 23245 |
| Descriptor | PT25-2 heavy chain, MAGNESIUM ION, PT25-2 light chain, ... (11 entities in total) |
| Functional Keywords | pt25-2, cell adhesion |
| Biological source | Mus musculus More |
| Total number of polymer chains | 4 |
| Total formula weight | 249590.66 |
| Authors | Bush, M.W.,Walz, T.,Coller, B.,Filizola, M.,Spasic, A.,Nesic, D.,Li, J. (deposition date: 2021-01-05, release date: 2022-01-12, Last modification date: 2025-06-04) |
| Primary citation | Nesic, D.,Bush, M.,Spasic, A.,Li, J.,Kamata, T.,Handa, M.,Filizola, M.,Walz, T.,Coller, B.S. Electron microscopy shows that binding of monoclonal antibody PT25-2 primes integrin alpha IIb beta 3 for ligand binding. Blood Adv, 5:1781-1790, 2021 Cited by PubMed Abstract: The murine monoclonal antibody (mAb) PT25-2 induces αIIbβ3 to bind ligand and initiate platelet aggregation. The underlying mechanism is unclear, because previous mutagenesis studies suggested that PT25-2 binds to the αIIb β propeller, a site distant from the Arg-Gly-Asp-binding pocket. To elucidate the mechanism, we studied the αIIbβ3-PT25-2 Fab complex by negative-stain and cryo-electron microscopy (EM). We found that PT25-2 binding results in αIIbβ3 partially exposing multiple ligand-induced binding site epitopes and adopting extended conformations without swing-out of the β3 hybrid domain. The cryo-EM structure showed PT25-2 binding to the αIIb residues identified by mutagenesis but also to 2 additional regions. Overlay of the cryo-EM structure with the bent αIIbβ3 crystal structure showed that binding of PT25-2 creates clashes with the αIIb calf-1/calf-2 domains, suggesting that PT25-2 selectively binds to partially or fully extended receptor conformations and prevents a return to its bent conformation. Kinetic studies of the binding of PT25-2 compared with mAbs 10E5 and 7E3 support this hypothesis. We conclude that PT25-2 induces αIIbβ3 ligand binding by binding to extended conformations and by preventing the interactions between the αIIb and β3 leg domains and subsequently the βI and β3 leg domains required for the bent-closed conformation. PubMed: 33760023DOI: 10.1182/bloodadvances.2020004166 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.3 Å) |
Structure validation
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