Enzyme inhibition by allosteric capture of an inactive conformation.

Autor: Lee GM; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158-2280, USA., Shahian T, Baharuddin A, Gable JE, Craik CS
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2011 Sep 02; Vol. 411 (5), pp. 999-1016. Date of Electronic Publication: 2011 Jun 22.
DOI: 10.1016/j.jmb.2011.06.032
Abstrakt: 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.
(Copyright © 2011 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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