4IRZ

Crystal structure of A4b7 headpiece complexed with Fab Natalizumab

Summary for 4IRZ

• Entry DOI: 10.2210/pdb4irz/pdb
• Descriptor: Integrin alpha4 subunit, Fab Natalizumab light chain, Fab Natalizumab heavy chain, ... (10 entities in total)
• Functional Keywords: rolling and firm adhesion, madcam, immune system
• Biological source: Oryctolagus cuniculus; More
• Total number of polymer chains: 3
• Total formula weight: 114852.40

Authors

Yu, Y.,Schurpf, T.,Springer, T.A. (deposition date: 2013-01-15, release date: 2013-09-25, Last modification date: 2024-10-30)

Primary citation

Yu, Y.,Schurpf, T.,Springer, T.A.
How natalizumab binds and antagonizes alpha 4 integrins.
J.Biol.Chem., 288:32314-32325, 2013

PubMed Abstract: Natalizumab antibody to α4-integrins is used in therapy of multiple sclerosis and Crohn's disease. A crystal structure of the Fab bound to an α4 integrin β-propeller and thigh domain fragment shows that natalizumab recognizes human-mouse differences on the circumference of the β-propeller domain. The epitope is adjacent to but outside of a ligand-binding groove formed at the interface with the β-subunit βI domain and shows no difference in structure when bound to Fab. Competition between Fab and the ligand vascular cell adhesion molecule (VCAM) for binding to cell surface α4β1 shows noncompetitive antagonism. In agreement, VCAM docking models suggest that binding of domain 1 of VCAM to α4-integrins is unimpeded by the Fab, and that bound Fab requires a change in orientation between domains 1 and 2 of VCAM for binding to α4β1. Mapping of species-specific differences onto α4β1 and α4β7 shows that their ligand-binding sites are highly conserved. Skewing away from these conserved regions of the epitopes recognized by current therapeutic function-blocking antibodies has resulted in previously unanticipated mechanisms of action.

PubMed: 24047894
DOI: 10.1074/jbc.M113.501668

Experimental method

X-RAY DIFFRACTION (2.84 Å)