Rationally Designed PI3Kα Mutants to Mimic ATR and Their Use to Understand Binding Specificity of ATR Inhibitors
Autor: | Johanna M. Jansen, Yipin Lu, Albert Lai, Isabel Zaror, Michael Doyle, Gwynn Pardee, Dirksen E. Bussiere, Sylvia Ma, Robert Elling, Kenneth Crawford, Janet Sim, Mulugeta Mamo, Yue Pan, Mark Knapp, Paul A. Barsanti, Kelly Yan, Elizabeth Ornelas, Warne Robert L, Li Zhang |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Models Molecular Class I Phosphatidylinositol 3-Kinases Protein Conformation Cell Mutant Ataxia Telangiectasia Mutated Proteins Biology Crystallography X-Ray 03 medical and health sciences Phosphatidylinositol 3-Kinases 0302 clinical medicine Structural Biology medicine Amino acid residue Molecular Biology Binding selectivity Binding Sites Kinase A protein Anticancer drug 030104 developmental biology medicine.anatomical_structure Biochemistry 030220 oncology & carcinogenesis Mutant Proteins biological phenomena cell phenomena and immunity Protein Binding |
Zdroj: | Journal of molecular biology. 429(11) |
ISSN: | 1089-8638 |
Popis: | ATR, a protein kinase in the PIKK family, plays a critical role in the cell DNA-damage response and is an attractive anticancer drug target. Several potent and selective inhibitors of ATR have been reported showing significant antitumor efficacy, with most advanced ones entering clinical trials. However, due to the absence of an experimental ATR structure, the determinants contributing to ATR inhibitors' potency and specificity are not well understood. Here we present the mutations in the ATP-binding site of PI3Kα to progressively transform the pocket to mimic that of ATR. The generated PI3Kα mutants exhibit significantly improved affinity for selective ATR inhibitors in multiple chemical classes. Furthermore, we obtained the X-ray structures of the PI3Kα mutants in complex with the ATR inhibitors. The crystal structures together with the analysis on the inhibitor affinity profile elucidate the roles of individual amino acid residues in the binding of ATR inhibitors, offering key insights for the binding mechanism and revealing the structure features important for the specificity of ATR inhibitors. The ability to obtain structural and binding data for these PI3Kα mutants, together with their ATR-like inhibitor binding profiles, makes these chimeric PI3Kα proteins valuable model systems for structure-based inhibitor design. |
Databáze: | OpenAIRE |
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