6QAV
Crystal structure of ULK2 in complexed with MRT68921
6QAV の概要
エントリーDOI | 10.2210/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 | Chaikuad, A.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Knapp, S.,Structural Genomics Consortium,Structural Genomics Consortium (SGC) (登録日: 2018-12-19, 公開日: 2019-02-27, 最終更新日: 2024-01-24) |
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: 30782972DOI: 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) |
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