Unraveling the allosteric mechanism of serine protease inhibition by an antibody

Structure. 2009 Dec 9;17(12):1614-1624. doi: 10.1016/j.str.2009.09.014.


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 A 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Allosteric Regulation
  • Amino Acid Sequence
  • Antibodies / chemistry
  • Antibodies / pharmacology*
  • Kinetics
  • Models, Molecular
  • Molecular Sequence Data
  • Sequence Homology, Amino Acid
  • Serine Proteases / immunology*
  • Serine Proteases / metabolism
  • Serine Proteinase Inhibitors / pharmacology*


  • Antibodies
  • Serine Proteinase Inhibitors
  • Serine Proteases