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

Structure. 2015 Jan 6;23(1):104-115. doi: 10.1016/j.str.2014.10.012. Epub 2014 Dec 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / chemistry
  • Antibodies / metabolism*
  • Catalytic Domain
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Crystallography, X-Ray
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Immunoglobulin Fab Fragments / chemistry
  • Immunoglobulin Fab Fragments / metabolism
  • Matrix Metalloproteinase 14 / chemistry*
  • Matrix Metalloproteinase 14 / metabolism*
  • Matrix Metalloproteinase Inhibitors / chemistry
  • Matrix Metalloproteinase Inhibitors / metabolism*
  • Models, Molecular
  • Protein Binding
  • Protein Structure, Quaternary

Substances

  • Antibodies
  • Immunoglobulin Fab Fragments
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinase 14