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

Research output: Contribution to journalArticlepeer-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 languageEnglish
Pages (from-to)104-115
Number of pages12
JournalStructure
Volume23
Issue number1
DOIs
StatePublished - 6 Jan 2015

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Structural Biology

Fingerprint

Dive into the research topics of 'Inhibition mechanism of membrane metalloprotease by an exosite-swiveling conformational antibody'. Together they form a unique fingerprint.

Cite this