5UKJ

The co-structure of N,N-dimethyl-4-[(6R)-6-methyl-5-(1H-pyrrolo[2,3- b]pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl]benzenesulfonamide and a rationally designed PI3K-alpha mutant that mimics ATR

Summary for 5UKJ

• Entry DOI: 10.2210/pdb5ukj/pdb
• Related: 5UK8 5UL1
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, N,N-dimethyl-4-[(6R)-6-methyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]benzenesulfonamide, ... (4 entities in total)
• Functional Keywords: inhibitor, lipid kinase, mutation, atr, transferase-signaling protein-inhibitor complex, transferase/signaling protein/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 160823.12

Authors

Knapp, M.S.,Elling, R.A.,Mamo, M. (deposition date: 2017-01-23, release date: 2017-05-10, Last modification date: 2024-04-03)

Primary citation

Lu, Y.,Knapp, M.,Crawford, K.,Warne, R.,Elling, R.,Yan, K.,Doyle, M.,Pardee, G.,Zhang, L.,Ma, S.,Mamo, M.,Ornelas, E.,Pan, Y.,Bussiere, D.,Jansen, J.,Zaror, I.,Lai, A.,Barsanti, P.,Sim, J.
Rationally Designed PI3K alpha Mutants to Mimic ATR and Their Use to Understand Binding Specificity of ATR Inhibitors.
J. Mol. Biol., 429:1684-1704, 2017

PubMed Abstract: 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.

PubMed: 28433539
DOI: 10.1016/j.jmb.2017.04.006

Experimental method

X-RAY DIFFRACTION (2.8 Å)