6GY0

mPI3Kd IN COMPLEX WITH AZ3

6GY0 の概要

• エントリーDOI: 10.2210/pdb6gy0/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, ~{N}-[4-methyl-5-(1-oxidanylidene-7-sulfamoyl-isoindol-5-yl)-1,3-thiazol-2-yl]ethanamide (3 entities in total)
• 機能のキーワード: inhibitor, pi3k, transferase
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 108002.88

構造登録者

Petersen, J. (登録日: 2018-06-27, 公開日: 2019-02-06, 最終更新日: 2024-11-06)

主引用文献

Gangadhara, G.,Dahl, G.,Bohnacker, T.,Rae, R.,Gunnarsson, J.,Blaho, S.,Oster, L.,Lindmark, H.,Karabelas, K.,Pemberton, N.,Tyrchan, C.,Mogemark, M.,Wymann, M.P.,Williams, R.L.,Perry, M.W.D.,Papavoine, T.,Petersen, J.
A class of highly selective inhibitors bind to an active state of PI3K gamma.
Nat.Chem.Biol., 15:348-357, 2019

PubMed Abstract: We have discovered a class of PI3Kγ inhibitors exhibiting over 1,000-fold selectivity over PI3Kα and PI3Kβ. On the basis of X-ray crystallography, hydrogen-deuterium exchange-mass spectrometry and surface plasmon resonance experiments we propose that the cyclopropylethyl moiety displaces the DFG motif of the enzyme away from the adenosine tri-phosphate binding site, inducing a large conformational change in both the kinase- and helical domains of PI3Kγ. Site directed mutagenesis explained how the conformational changes occur. Our results suggest that these cyclopropylethyl substituted compounds selectively inhibit the active state of PI3Kγ, which is unique to these compounds and to the PI3Kγ isoform, explaining their excellent potency and unmatched isoform selectivity that were confirmed in cellular systems. This is the first example of a Class I PI3K inhibitor achieving its selectivity by affecting the DFG motif in a manner that bears similarity to DFG in/out for type II protein kinase inhibitors.

PubMed: 30718815
DOI: 10.1038/s41589-018-0215-0

実験手法

X-RAY DIFFRACTION (2.55 Å)