7JWZ

IPI-549 bound to the PI3Kg catalytic subunit p110 gamma

7JWZ の概要

• エントリーDOI: 10.2210/pdb7jwz/pdb
• 関連するPDBエントリー: 7JWE
• 分子名称: 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)
• 機能のキーワード: pi3k, inhibitor, phosphoinositides, p110, pik3cg, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 111255.67

構造登録者

Burke, J.E.,Rathinaswamy, M.K.,Harris, N.J. (登録日: 2020-08-26, 公開日: 2021-03-17, 最終更新日: 2023-10-18)

主引用文献

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

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: 33661099
DOI: 10.7554/eLife.64691

実験手法

X-RAY DIFFRACTION (2.65 Å)