6HJJ

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

Summary for 6HJJ

• Entry DOI: 10.2210/pdb6hjj/pdb
• Descriptor: 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)
• Functional Keywords: protein kinase, mitosis, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 33878.89

Authors

Bayliss, R.,McIntyre, P.J. (deposition date: 2018-09-04, release date: 2018-10-03, Last modification date: 2024-05-15)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.13 Å)