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

Yael Udi; Moran Grossman; Inna Solomonov; Orly Dym; Haim Rozenberg; Vanessa Moreno; Philippe Cuniasse; Vincent Dive; Alicia García Arroyo; Irit Sagi

doi:10.1016/j.str.2014.10.012

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

Yael Udi, Moran Grossman, Inna Solomonov, Orly Dym, Haim Rozenberg, Vanessa Moreno, Philippe Cuniasse, Vincent Dive, Alicia García Arroyo, Irit Sagi

Weizmann Institute of Science

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	104-115
Number of pages	12
Journal	Structure
Volume	23
Issue number	1
DOIs	https://doi.org/10.1016/j.str.2014.10.012
State	Published - 6 Jan 2015

All Science Journal Classification (ASJC) codes

Structural Biology
Molecular Biology

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10.1016/j.str.2014.10.012

Cite this

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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.",

author = "Yael Udi and Moran Grossman and Inna Solomonov and Orly Dym and Haim Rozenberg and Vanessa Moreno and Philippe Cuniasse and Vincent Dive and Arroyo, {Alicia Garc{\'i}a} and Irit Sagi",

year = "2015",

month = jan,

day = "6",

doi = "10.1016/j.str.2014.10.012",

language = "الإنجليزيّة",

volume = "23",

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journal = "Structure",

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TY - JOUR

T1 - Inhibition mechanism of membrane metalloprotease by an exosite-swiveling conformational antibody

AU - Udi, Yael

AU - Grossman, Moran

AU - Solomonov, Inna

AU - Dym, Orly

AU - Rozenberg, Haim

AU - Moreno, Vanessa

AU - Cuniasse, Philippe

AU - Dive, Vincent

AU - Arroyo, Alicia García

AU - Sagi, Irit

PY - 2015/1/6

Y1 - 2015/1/6

N2 - 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.

AB - 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.

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U2 - 10.1016/j.str.2014.10.012

DO - 10.1016/j.str.2014.10.012

M3 - مقالة

SN - 0969-2126

VL - 23

SP - 104

EP - 115

JO - Structure

JF - Structure

IS - 1

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

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