title: Inhibition mechanism of membrane metalloprotease by an exosite-swiveling conformational antibody.
abstract: 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.
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Udi
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Moran
authors.initials: M
authors.lastname: Grossman
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Solomonov
authors.affiliation: Structural Proteomics Unit and Department of Structural Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Dym
authors.affiliation: Structural Proteomics Unit and Department of Structural Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Rozenberg
authors.affiliation: Vascular Biology and Inflammation Department, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, Madrid 28029, Spain.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Moreno
authors.affiliation: Commissariat à l'Énergie Atomique et aux Énergies Alternatives (CEA), Service d'Ingénierie Moléculaire de Protéines, Gif/Yvette 91191, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Cuniasse
authors.affiliation: Commissariat à l'Énergie Atomique et aux Énergies Alternatives (CEA), Service d'Ingénierie Moléculaire de Protéines, Gif/Yvette 91191, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
authors.affiliation: Vascular Biology and Inflammation Department, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, Madrid 28029, Spain.
authors.forename: Alicia García
authors.initials: AG
authors.lastname: Arroyo
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: irit.sagi@weizmann.ac.il.
authors.forename: Irit
authors.initials: I
authors.lastname: Sagi
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry* / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary
chemical_list: D000906:Antibodies; D007140:Immunoglobulin Fab Fragments; D061965:Matrix Metalloproteinase Inhibitors; D053511:Matrix Metalloproteinase 14