Enzyme inhibition by allosteric capture of an inactive conformation

J Mol Biol. 2011 Sep 2;411(5):999-1016. doi: 10.1016/j.jmb.2011.06.032. Epub 2011 Jun 22.


All members of the human herpesvirus protease (HHV Pr) family are active as weakly associating dimers but inactive as monomers. A small-molecule allosteric inhibitor of Kaposi's sarcoma-associated herpesvirus protease (KSHV Pr) traps the enzyme in an inactive monomeric state where the C-terminal helices are unfolded and the hydrophobic dimer interface is exposed. NMR titration studies demonstrate that the inhibitor binds to KSHV Pr monomers with low micromolar affinity. A 2.0-Å-resolution X-ray crystal structure of a C-terminal truncated KSHV Pr-inhibitor complex locates the binding pocket at the dimer interface and displays significant conformational perturbations at the active site, 15 Å from the allosteric site. NMR and CD data suggest that the small molecule inhibits human cytomegalovirus protease via a similar mechanism. As all HHV Prs are functionally and structurally homologous, the inhibitor represents a class of compounds that may be developed into broad-spectrum therapeutics that allosterically regulate enzymatic activity by disrupting protein-protein interactions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Site
  • Binding Sites
  • Catalytic Domain
  • Circular Dichroism
  • Crystallography, X-Ray
  • Dimerization
  • Enzyme Inhibitors / metabolism*
  • Herpesvirus 8, Human / enzymology*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Mutagenesis
  • Protein Binding
  • Protein Conformation
  • Serine Endopeptidases / chemistry*
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*


  • Enzyme Inhibitors
  • Serine Endopeptidases
  • assemblin
  • human herpesvirus 8 protease

Associated data

  • PDB/3NJQ