ATP-competitive inhibitors modulate the substrate binding cooperativity of a kinase by altering its conformational entropy
| Autor: | Olivieri, Cristina, Li, Geoffrey C, Wang, Yingjie, V S, Manu, Walker, Caitlin, Kim, Jonggul, Camilloni, Carlo, De Simone, Alfonso, Vendruscolo, Michele, Bernlohr, David A, Taylor, Susan S, Veglia, Gianluigi |
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| Přispěvatelé: | Olivieri, C., Li, G. C., Wang, Y., Manu, V. S., Walker, C., Kim, J., Camilloni, C., De Simone, A., Vendruscolo, M., Bernlohr, D. A., Taylor, S. S., Veglia, G., Olivieri, Cristina [0000-0001-6957-6743], Li, Geoffrey C [0000-0001-5035-5916], Wang, Yingjie [0000-0001-9800-8163], V S, Manu [0000-0002-1374-2797], Walker, Caitlin [0000-0003-0977-8276], Kim, Jonggul [0000-0002-4624-7848], Camilloni, Carlo [0000-0002-9923-8590], Vendruscolo, Michele [0000-0002-3616-1610], Bernlohr, David A [0000-0001-6969-9129], Taylor, Susan S [0000-0002-7702-6108], Veglia, Gianluigi [0000-0002-2795-6964], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
4613 Theory Of Computation
Multidisciplinary 34 Chemical Sciences 46 Information and Computing Sciences 5.1 Pharmaceuticals Settore BIO/10 - Biochimica Generic health relevance 3404 Medicinal and Biomolecular Chemistry 3101 Biochemistry and Cell Biology 5 Development of treatments and therapeutic interventions Settore FIS/07 - Fisica Applicata(Beni Culturali Ambientali Biol.e Medicin) 31 Biological Sciences |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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