6HJJ

Crystal structure of Aurora-A L210C catalytic domain in complex with ASDO6 ligand

6HJJ の概要

• エントリーDOI: 10.2210/pdb6hjj/pdb
• 分子名称: Aurora kinase A, ~{N}-[4-(4-azanyl-1-propan-2-yl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-methyl-phenyl]-4-[4-fluoranyl-3-(trifluoromethyl)phenyl]-4-oxidanylidene-butanamide, CHLORIDE ION, ... (6 entities in total)
• 機能のキーワード: protein kinase, mitosis, transferase
• 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: 33878.89

構造登録者

Bayliss, R.,McIntyre, P.J. (登録日: 2018-09-04, 公開日: 2018-10-03, 最終更新日: 2024-05-15)

主引用文献

Ocasio, C.A.,Warkentin, A.A.,McIntyre, P.J.,Barkovich, K.J.,Vesely, C.,Spencer, J.,Shokat, K.M.,Bayliss, R.
Type II Kinase Inhibitors Targeting Cys-Gatekeeper Kinases Display Orthogonality with Wild Type and Ala/Gly-Gatekeeper Kinases.
ACS Chem. Biol., 13:2956-2965, 2018

PubMed Abstract: Analogue-sensitive (AS) kinases contain large to small mutations in the gatekeeper position rendering them susceptible to inhibition with bulky analogues of pyrazolopyrimidine-based Src kinase inhibitors (e.g., PP1). This "bump-hole" method has been utilized for at least 85 of ∼520 kinases, but many kinases are intolerant to this approach. To expand the scope of AS kinase technology, we designed type II kinase inhibitors, ASDO2/6 (analogue-sensitive "DFG-out" kinase inhibitors 2 and 6), that target the "DFG-out" conformation of Cys-gatekeeper kinases with submicromolar potency. We validated this system in vitro against Greatwall kinase (GWL), Aurora-A kinase, and cyclin-dependent kinase-1 and in cells using M110C-GWL-expressing mouse embryonic fibroblasts. These Cys-gatekeeper kinases were sensitive to ASDO2/6 inhibition but not AS kinase inhibitor 3MB-PP1 and vice versa. These compounds, with AS kinase inhibitors, have the potential to inhibit multiple AS kinases independently with applications in systems level and translational kinase research as well as the rational design of type II kinase inhibitors targeting endogenous kinases.

PubMed: 30239186
DOI: 10.1021/acschembio.8b00592

実験手法

X-RAY DIFFRACTION (2.13 Å)