3QA3

Crystal Structure of A-domain in complex with antibody

Summary for 3QA3

• Entry DOI: 10.2210/pdb3qa3/pdb
• Related: 3Q3G
• Descriptor: Antibody Light chain, Antibody Heavy chain, Integrin alpha-M, ... (7 entities in total)
• Functional Keywords: immune system- cell adhesion complex, immune system/ cell adhesion
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P11215
• Total number of polymer chains: 12
• Total formula weight: 282011.89

Authors

Mahalingam, B.,Xiong, J.P.,Arnaout, M.A. (deposition date: 2011-01-10, release date: 2011-11-30, Last modification date: 2024-10-09)

Primary citation

Mahalingam, B.,Ajroud, K.,Alonso, J.L.,Anand, S.,Adair, B.D.,Horenstein, A.L.,Malavasi, F.,Xiong, J.P.,Arnaout, M.A.
Stable Coordination of the Inhibitory Ca2+ Ion at the Metal Ion-Dependent Adhesion Site in Integrin CD11b/CD18 by an Antibody-Derived Ligand Aspartate: Implications for Integrin Regulation and Structure-Based Drug Design.
J.Immunol., 187:6393-6401, 2011

PubMed Abstract: A central feature of integrin interaction with physiologic ligands is the monodentate binding of a ligand carboxylate to a Mg(2+) ion hexacoordinated at the metal ion-dependent adhesion site (MIDAS) in the integrin A domain. This interaction stabilizes the A domain in the high-affinity state, which is distinguished from the default low-affinity state by tertiary changes in the domain that culminate in cell adhesion. Small molecule ligand-mimetic integrin antagonists act as partial agonists, eliciting similar activating conformational changes in the A domain, which has contributed to paradoxical adhesion and increased patient mortality in large clinical trials. As with other ligand-mimetic integrin antagonists, the function-blocking mAb 107 binds MIDAS of integrin CD11b/CD18 A domain (CD11bA), but in contrast, it favors the inhibitory Ca(2+) ion over the Mg(2+) ion at MIDAS. We determined the crystal structures of the Fab fragment of mAb 107 complexed to the low- and high-affinity states of CD11bA. Favored binding of the Ca(2+) ion at MIDAS is caused by the unusual symmetric bidentate ligation of a Fab-derived ligand Asp to a heptacoordinated MIDAS Ca(2+) ion. Binding of the Fab fragment of mAb 107 to CD11bA did not trigger the activating tertiary changes in the domain or in the full-length integrin. These data show that the denticity of the ligand Asp/Glu can modify the divalent cation selectivity at MIDAS and hence integrin function. Stabilizing the Ca(2+) ion at MIDAS by bidentate ligation to a ligand Asp/Glu may provide one approach for designing pure integrin antagonists.

PubMed: 22095715
DOI: 10.4049/jimmunol.1102394

Experimental method

X-RAY DIFFRACTION (3 Å)