Inhibition mechanism of membrane metalloprotease by an exosite-swiveling conformational antibody.

Yael Udi (1) , Moran Grossman (1) , Inna Solomonov (1) , Orly Dym (1) , Haim Rozenberg (1) , Vanessa Moreno (2) , Philippe Cuniasse (3, 4) , Vincent Dive (4) , Alicia García Arroyo (2) , Irit Sagi (1)

1 Weizmann Institute of Science [Rehovot, Israël]
2 Vascular Biology and Inflammation Department
3 INTGEN - Enveloppe Nucléaire, Télomères et Réparation de l’ADN
4 SIMoS - Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)

Membrane type 1 metalloprotease (MT1-MMP) is a membrane-anchored, zinc-dependent protease. MT1-MMP is an important mediator of cell migration and invasion, and overexpression of this enzyme has been correlated with the malignancy of various tumor types. Therefore, modulators of MT1-MMP activity are proposed to possess therapeutic potential in numerous invasive diseases. Here we report the inhibition mode of MT1-MMP by LEM-2/15 antibody, which targets a surface epitope of MT1-MMP. Specifically, the crystal structures of Fab LEM-2/15 in complex with the MT1-MMP surface antigen suggest that conformational swiveling of the enzyme surface loop is required for effective binding and consequent inhibition of MT1-MMP activity on the cell membrane. This inhibition mechanism appears to be effective in controlling active MT1-MMP in endothelial cells and at the leading edge of migratory cancer cells.

Domaines: Sciences du Vivant [q-bio]

Yael Udi, Moran Grossman, Inna Solomonov, Orly Dym, Haim Rozenberg, et al.. Inhibition mechanism of membrane metalloprotease by an exosite-swiveling conformational antibody.. Structure (London, England : 1993), 2015, 23 (1), pp.104-15. ⟨10.1016/j.str.2014.10.012⟩. ⟨hal-01449558⟩