4OYS

CRYSTAL STRUCTURE OF VPS34 IN COMPLEX WITH SAR405.

4OYS の概要

• エントリーDOI: 10.2210/pdb4oys/pdb
• 分子名称: Phosphatidylinositol 3-kinase catalytic subunit type 3, SULFATE ION, (8S)-9-[(5-chloranylpyridin-3-yl)methyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(trifluoromethyl)-6,7,8,9a-tetrahydro-3H-pyrimido[1,2-a]pyrimidin-4-one, ... (4 entities in total)
• 機能のキーワード: lipid kinase
• 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: 69427.51

構造登録者

Mathieu, M.,Marquette, J.p. (登録日: 2014-02-13, 公開日: 2014-10-22, 最終更新日: 2024-03-27)

主引用文献

Ronan, B.,Flamand, O.,Vescovi, L.,Dureuil, C.,Durand, L.,Fassy, F.,Bachelot, M.F.,Lamberton, A.,Mathieu, M.,Bertrand, T.,Marquette, J.P.,El-Ahmad, Y.,Filoche-Romme, B.,Schio, L.,Garcia-Echeverria, C.,Goulaouic, H.,Pasquier, B.
A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy.
Nat.Chem.Biol., 10:1013-1019, 2014

PubMed Abstract: Vps34 is a phosphoinositide 3-kinase (PI3K) class III isoform that has attracted major attention over the recent years because of its role in autophagy. Herein we describe the biological characterization of SAR405, which is a low-molecular-mass kinase inhibitor of Vps34 (KD 1.5 nM). This compound has an exquisite protein and lipid kinase selectivity profile that is explained by its unique binding mode and molecular interactions within the ATP binding cleft of human Vps34. To the best of our knowledge, this is the first potent and specific Vps34 inhibitor described so far. Our results demonstrate that inhibition of Vps34 kinase activity by SAR405 affects both late endosome-lysosome compartments and prevents autophagy. Moreover, we show that the concomitant inhibition of Vps34 and mTOR, with SAR405 and the US Food and Drug Administration-approved mTOR inhibitor everolimus, results in synergistic antiproliferative activity in renal tumor cell lines, indicating a potential clinical application in cancer.

PubMed: 25326666
DOI: 10.1038/nchembio.1681

実験手法

X-RAY DIFFRACTION (2.9 Å)