title: Enzyme inhibition by allosteric capture of an inactive conformation.
abstract: 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.
authors: Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158-2280, USA.
authors: Gregory M
authors: GM
authors: Lee
authors: Tina
authors: T
authors: Shahian
authors: Aida
authors: A
authors: Baharuddin
authors: Jonathan E
authors: JE
authors: Gable
authors: Charles S
authors: CS
authors: Craik
mesh_terms: D000495:Allosteric Site; D001665:Binding Sites; D020134:Catalytic Domain; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000201:enzymology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D016296:Mutagenesis; D011485:Protein Binding; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D012697:Serine Endopeptidases; C071910:assemblin; C107889:human herpesvirus 8 protease