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J Mol Biol. 2007 Jun 15;369(4):1041-51. Epub 2007 Apr 4.

The mechanism of inhibition of antibody-based inhibitors of membrane-type serine protease 1 (MT-SP1).

Author information

1
Graduate Group in Biophysics, University of California, San Francisco, 600 16th St. Genentech Hall, San Francisco, CA 94143, USA.

Abstract

The mechanisms of inhibition of two novel scFv antibody inhibitors of the serine protease MT-SP1/matriptase reveal the basis of their potency and specificity. Kinetic experiments characterize the inhibitors as extremely potent inhibitors with K(I) values in the low picomolar range that compete with substrate binding in the S1 site. Alanine scanning of the loops surrounding the protease active site provides a rationale for inhibitor specificity. Each antibody binds to a number of residues flanking the active site, forming a unique three-dimensional binding epitope. Interestingly, one inhibitor binds in the active site cleft in a substrate-like manner, can be processed by MT-SP1 at low pH, and is a standard mechanism inhibitor of the protease. The mechanisms of inhibition provide a rationale for the effectiveness of these inhibitors, and suggest that the development of specific antibody-based inhibitors against individual members of closely related enzyme families is feasible, and an effective way to develop tools to tease apart complex biological processes.

PMID:
17475279
PMCID:
PMC2041882
DOI:
10.1016/j.jmb.2007.03.078
[Indexed for MEDLINE]
Free PMC Article

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