Antibodies display great versatility in protein interactions and have become important therapeutic agents for a variety of human diseases. Their ability to discriminate between highly conserved sequences could be of great use for therapeutic approaches that target proteases, for which structural features are conserved among family members. Recent crystal structures of antibody–protease complexes provide exciting insight into the variety of ways antibodies can interfere with the catalytic machinery of serine proteases. The studies revealed the molecular details of two fundamental mechanisms by which antibodies inhibit catalysis of trypsin-like serine proteases, exemplified by hepatocyte growth factor activator and MT-SP1 (matriptase). Enzyme kinetics defines both mechanisms as competitive inhibition systems, yet, on the molecular level, they involve distinct structural elements of the active-site region. In the steric hindrance mechanism, the antibody binds to protruding surface loops and inserts one or two CDR (complementarity-determining region) loops into the enzyme's substrate-binding cleft, which results in obstruction of substrate access. In the allosteric inhibition mechanism the antibody binds outside the active site at the periphery of the substrate-binding cleft and, mediated through a conformational change of a surface loop, imposes structural changes at important substrate interaction sites resulting in impaired catalysis. At the centre of this allosteric mechanism is the 99-loop, which is sandwiched between the substrate and the antibody-binding sites and serves as a mobile conduit between these sites. These findings provide comprehensive structural and functional insight into the molecular versatility of antibodies for interfering with the catalytic machinery of proteases.
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September 2010
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Review Article|
August 13 2010
Structural and mechanistic insight into how antibodies inhibit serine proteases
Rajkumar Ganesan;
Rajkumar Ganesan
*Department of Protein Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
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Charles Eigenbrot;
Charles Eigenbrot
†Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
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Daniel Kirchhofer
Daniel Kirchhofer
1
*Department of Protein Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
1To whom correspondence should be addressed (email dak@gene.com).
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Publisher: Portland Press Ltd
Received:
April 27 2010
Revision Received:
June 11 2010
Accepted:
June 14 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 430 (2): 179–189.
Article history
Received:
April 27 2010
Revision Received:
June 11 2010
Accepted:
June 14 2010
Citation
Rajkumar Ganesan, Charles Eigenbrot, Daniel Kirchhofer; Structural and mechanistic insight into how antibodies inhibit serine proteases. Biochem J 1 September 2010; 430 (2): 179–189. doi: https://doi.org/10.1042/BJ20100634
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