ATP-competitive inhibitors modulate the substrate binding cooperativity of a kinase by altering its conformational entropy.

ABSTRACT: ATP-competitive inhibitors are currently the largest class of clinically approved drugs for protein kinases. By targeting the ATP-binding pocket, these compounds block the catalytic activity, preventing substrate phosphorylation. A problem with these drugs, however, is that inhibited kinases may still recognize and bind downstream substrates, acting as scaffolds or binding hubs for signaling partners. Here, using protein kinase A as a model system, we show that chemically different ATP-competitive inhibitors modulate the substrate binding cooperativity by tuning the conformational entropy of the kinase and shifting the populations of its conformationally excited states. Since we found that binding cooperativity and conformational entropy of the enzyme are correlated, we propose a new parad

SUBMITTER: Olivieri C 

PROVIDER: S-EPMC9337769 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature