Loading
PDBj
メニューPDBj@FacebookPDBj@TwitterPDBj@YouTubewwPDB FoundationwwPDB
RCSB PDBPDBeBMRBAdv. SearchSearch help

6QAV

Crystal structure of ULK2 in complexed with MRT68921

6QAV の概要
エントリーDOI10.2210/pdb6qav/pdb
分子名称Serine/threonine-protein kinase ULK2, ~{N}-[3-[[5-cyclopropyl-2-[(2-methyl-3,4-dihydro-1~{H}-isoquinolin-6-yl)amino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide, 1,2-ETHANEDIOL, ... (6 entities in total)
機能のキーワードulk2, autophagy, kinase, inhibitor complex, structural genomics, structural genomics consortium, sgc, transferase
由来する生物種Homo sapiens (Human)
タンパク質・核酸の鎖数4
化学式量合計129947.39
構造登録者
主引用文献Chaikuad, A.,Koschade, S.E.,Stolz, A.,Zivkovic, K.,Pohl, C.,Shaid, S.,Ren, H.,Lambert, L.J.,Cosford, N.D.P.,Brandts, C.H.,Knapp, S.
Conservation of structure, function and inhibitor binding in UNC-51-like kinase 1 and 2 (ULK1/2).
Biochem.J., 476:875-887, 2019
Cited by
PubMed Abstract: Autophagy is essential for cellular homeostasis and when deregulated this survival mechanism has been associated with disease development. Inhibition of autophagy initiation by inhibiting the kinase ULK1 (Unc-51-like autophagy activating kinase 1) has been proposed as a potential cancer therapy. While inhibitors and crystal structures of ULK1 have been reported, little is known about the other closely related kinase ULK2 (Unc-51-like autophagy activating kinase 2). Here, we present the crystal structure of ULK2 in complex with ATP competitive inhibitors. Surprisingly, the ULK2 structure revealed a dimeric assembly reminiscent of dimeric arrangements of auto-activating kinases suggesting a role for this association in ULK activation. Screening of a kinase focused library of pre-clinical and clinical compounds revealed several potent ULK1/2 inhibitors and good correlation of inhibitor-binding behavior with both ULK kinases. Aurora A was identified as a major off-target of currently used ULK1 inhibitors. Autophagic flux assays demonstrated that this off-target activity by strongly inducing autophagy in different cellular systems conferred an additional layer of complexity in the interpretation of cellular data. The data presented here provide structural models and chemical starting points for the development of ULK1/2 dual inhibitors with improved selectivity for future exploitation of autophagy inhibition.
PubMed: 30782972
DOI: 10.1042/BCJ20190038
主引用文献が同じPDBエントリー
実験手法
X-RAY DIFFRACTION (2.05 Å)
構造検証レポート
Validation report summary of 6qav
検証レポート(詳細版)ダウンロードをダウンロード

226707

件を2024-10-30に公開中

PDB statisticsPDBj update infoContact PDBjnumon