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 paradigm for the discovery of ATP-competitive inhibitors, which is based on their ability to modulate the allosteric coupling between nucleotide and substrate-binding sites.

ATP-competitive inhibitors modulate the substrate binding cooperativity of a kinase by altering its conformational entropy / C. Olivieri, G.C. Li, Y. Wang, M. V S, C. Walker, J. Kim, C. Camilloni, A. De Simone, M. Vendruscolo, D.A. Bernlohr, S.S. Taylor, G. Veglia. - In: SCIENCE ADVANCES. - ISSN 2375-2548. - 8:30(2022 Jul 29), pp. eabo0696.1-eabo0696.13. [10.1126/sciadv.abo0696]

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

C. Camilloni;
2022

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 paradigm for the discovery of ATP-competitive inhibitors, which is based on their ability to modulate the allosteric coupling between nucleotide and substrate-binding sites.
Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)
Settore BIO/10 - Biochimica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/937028
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