Journal
STRUCTURE
Volume 17, Issue 12, Pages 1614-1624Publisher
CELL PRESS
DOI: 10.1016/j.str.2009.09.014
Keywords
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Funding
- Department of Energy, Office of Biological and Environmental Research
- National Institutes of Health, National Center for Research Resources
- National Institute of General Medical Sciences
- Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-AC0205CH1231]
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Recent structural studies have outlined the mechanism of protease inhibition by active site-directed antibodies. However, the molecular basis of allosteric inhibition by antibodies has been elusive. Here we report the 2.35 angstrom resolution structure of the trypsin-like serine protease hepatocyte growth factor activator (HGFA) in complex with the allosteric antibody Ab40, a potent inhibitor of HGFA catalytic activity. The antibody binds at the periphery of the substrate binding cleft and imposes a conformational change on the entire 99-loop (chymotrypsinogen numbering). The altered conformation of the 99-loop is incompatible with substrate binding due to the partial collapse of subsite S2 and the reorganization of subsite S4. Remarkably, a single residue deletion of Ab40 abolished inhibition of HGFA activity, commensurate with the reversal of the 99-loop conformation to its competent state. The results define an allosteric switch mechanism as the basis of protease inhibition by an allosteric antibody.
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