6V4P

Structure of the integrin AlphaIIbBeta3-Abciximab complex

Summary for 6V4P

• Entry DOI: 10.2210/pdb6v4p/pdb
• EMDB information: 21044
• Descriptor: Integrin alpha-IIb, Integrin beta-3, Abciximab, heavy chain, ... (6 entities in total)
• Functional Keywords: integrin, abciximab, blood clotting, cell adhesion-immune system complex, cell adhesion/immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 228797.14

Authors

Nesic, D.,Zhang, Y.,Spasic, A.,Li, J.,Provasi, D.,Filizola, M.,Walz, T.,Coller, B.S. (deposition date: 2019-11-28, release date: 2020-02-05, Last modification date: 2024-10-30)

Primary citation

Nesic, D.,Zhang, Y.,Spasic, A.,Li, J.,Provasi, D.,Filizola, M.,Walz, T.,Coller, B.S.
Cryo-Electron Microscopy Structure of the alpha IIb beta 3-Abciximab Complex.
Arterioscler Thromb Vasc Biol., 40:624-637, 2020

PubMed Abstract: The αIIbβ3 antagonist antiplatelet drug abciximab is the chimeric antigen-binding fragment comprising the variable regions of murine monoclonal antibody 7E3 and the constant domains of human IgG1 and light chain κ. Previous mutagenesis studies suggested that abciximab binds to the β3 C177-C184 specificity-determining loop (SDL) and Trp129 on the adjacent β1-α1 helix. These studies could not, however, assess whether 7E3 or abciximab prevents fibrinogen binding by steric interference, disruption of either the αIIbβ3-binding pocket for fibrinogen or the β3 SDL (which is not part of the binding pocket but affects fibrinogen binding), or some combination of these effects. To address this gap, we used cryo-electron microscopy to determine the structure of the αIIbβ3-abciximab complex at 2.8 Å resolution. Approach and Results: The interacting surface of abciximab is comprised of residues from all 3 complementarity-determining regions of both the light and heavy chains, with high representation of aromatic residues. Binding is primarily to the β3 SDL and neighboring residues, the β1-α1 helix, and β3 residues Ser211, Val212 and Met335. Unexpectedly, the structure also indicated several interactions with αIIb. As judged by the cryo-electron microscopy model, molecular-dynamics simulations, and mutagenesis, the binding of abciximab does not appear to rely on the interaction with the αIIb residues and does not result in disruption of the fibrinogen-binding pocket; it does, however, compress and reduce the flexibility of the SDL.

PubMed: 31969014
DOI: 10.1161/ATVBAHA.119.313671

Experimental method

ELECTRON MICROSCOPY (2.8 Å)