Yu Y, Schürpf T, Springer TA.How Natalizumab Binds and Antagonizes α4 Integrins. J Biol Chem. 2013 Sep. [Epub ahead of print]
Natalizumab antibody to α4-integrins is used in therapy of multiple sclerosis. 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.
This study gives a molecular insight how tysabri works but at the end of the day it acts to block white cells getting into the CNS