7JWZ
IPI-549 bound to the PI3Kg catalytic subunit p110 gamma
Summary for 7JWZ
| Entry DOI | 10.2210/pdb7jwz/pdb |
| Related | 7JWE |
| Descriptor | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 2-amino-N-[(1S)-1-{8-[(1-methyl-1H-pyrazol-4-yl)ethynyl]-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl}ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (2 entities in total) |
| Functional Keywords | pi3k, inhibitor, phosphoinositides, p110, pik3cg, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 111255.67 |
| Authors | Burke, J.E.,Rathinaswamy, M.K.,Harris, N.J. (deposition date: 2020-08-26, release date: 2021-03-17, Last modification date: 2023-10-18) |
| Primary citation | Rathinaswamy, M.K.,Gaieb, Z.,Fleming, K.D.,Borsari, C.,Harris, N.J.,Moeller, B.J.,Wymann, M.P.,Amaro, R.E.,Burke, J.E. Disease related mutations in PI3K gamma disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors. Elife, 10:-, 2021 Cited by PubMed Abstract: Class I Phosphoinositide 3-kinases (PI3Ks) are master regulators of cellular functions, with the class IB PI3K catalytic subunit (p110γ) playing key roles in immune signalling. p110γ is a key factor in inflammatory diseases and has been identified as a therapeutic target for cancers due to its immunomodulatory role. Using a combined biochemical/biophysical approach, we have revealed insight into regulation of kinase activity, specifically defining how immunodeficiency and oncogenic mutations of R1021 in the C-terminus can inactivate or activate enzyme activity. Screening of inhibitors using HDX-MS revealed that activation loop-binding inhibitors induce allosteric conformational changes that mimic those in the R1021C mutant. Structural analysis of advanced PI3K inhibitors in clinical development revealed novel binding pockets that can be exploited for further therapeutic development. Overall, this work provides unique insights into regulatory mechanisms that control PI3Kγ kinase activity and shows a framework for the design of PI3K isoform and mutant selective inhibitors. PubMed: 33661099DOI: 10.7554/eLife.64691 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.65 Å) |
Structure validation
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