Unknown

Dataset Information

0

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.

SUBMITTER: Lee GM 

PROVIDER: S-EPMC3157250 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

altmetric image

Publications

Enzyme inhibition by allosteric capture of an inactive conformation.

Lee Gregory M GM   Shahian Tina T   Baharuddin Aida A   Gable Jonathan E JE   Craik Charles S CS  

Journal of molecular biology 20110622 5


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  ...[more]

Similar Datasets

| S-EPMC6219988 | biostudies-literature
| S-EPMC2633928 | biostudies-literature
| S-EPMC3047156 | biostudies-literature
| S-EPMC3365166 | biostudies-literature
| S-EPMC6437697 | biostudies-literature
| S-EPMC4973392 | biostudies-literature
| S-EPMC9013487 | biostudies-literature
| S-EPMC3742363 | biostudies-literature
| S-EPMC4818521 | biostudies-literature
| S-EPMC3899129 | biostudies-literature