Crystal structure of a4b7 headpiece complexed with fab natalizumab
Structure:
Integrin alpha4 subunit. Chain: a. Engineered: yes. Fab natalizumab light chain. Chain: l. Engineered: yes. Fab natalizumab heavy chain. Chain: h. Engineered: yes
How natalizumab binds and antagonizes α4 integrins.
Y.Yu,
T.Schürpf,
T.A.Springer.
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.
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