4QXU

Novel Inhibition Mechanism of Membrane Metalloprotease by an Exosite-Swiveling Conformational antibody

Summary for 4QXU

• Entry DOI: 10.2210/pdb4qxu/pdb
• Related: 4OUU 4P3C 4P3D
• Descriptor: anti_MT1-MMP Light chain, anti_MT1-MMP Heavy chain, Matrix metalloproteinase-14, ... (5 entities in total)
• Functional Keywords: structural genomics, psi-2, protein structure initiative, israel structural proteomics center, ispc, igg fold, immune system
• Biological source: Mus musculus (mouse); More
• Cellular location: Membrane ; Single-pass type I membrane protein : P50281
• Total number of polymer chains: 3
• Total formula weight: 50642.37

Authors

Udi, Y.,Grossman, M.,Solomonov, I.,Dym, O.,Rozenberg, H.,Moreno, v.,Cuiniasse, P.,Dive, V.,Arroyo, A.G.,Sagi, I.,Israel Structural Proteomics Center (ISPC) (deposition date: 2014-07-22, release date: 2014-12-17, Last modification date: 2024-10-16)

Primary citation

Udi, Y.,Grossman, M.,Solomonov, I.,Dym, O.,Rozenberg, H.,Moreno, V.,Cuniasse, P.,Dive, V.,Arroyo, A.G.,Sagi, I.
Inhibition mechanism of membrane metalloprotease by an exosite-swiveling conformational antibody.
Structure, 23:104-115, 2015

PubMed 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.

PubMed: 25482542
DOI: 10.1016/j.str.2014.10.012

Experimental method

X-RAY DIFFRACTION (2.3 Å)