6ATE

SRC kinase bound to covalent inhibitor

Summary for 6ATE

• Entry DOI: 10.2210/pdb6ate/pdb
• Descriptor: Proto-oncogene tyrosine-protein kinase Src, N-{2-[(5-chloro-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)amino]phenyl}propanamide (3 entities in total)
• Functional Keywords: kinase, phosphorylation, transferase-transferase inhibitor complex, transferase, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 33176.56

Authors

Gurbani, D.,Westover, K.D. (deposition date: 2017-08-28, release date: 2019-02-27, Last modification date: 2024-11-20)

Primary citation

Rao, S.,Gurbani, D.,Du, G.,Everley, R.A.,Browne, C.M.,Chaikuad, A.,Tan, L.,Schroder, M.,Gondi, S.,Ficarro, S.B.,Sim, T.,Kim, N.D.,Berberich, M.J.,Knapp, S.,Marto, J.A.,Westover, K.D.,Sorger, P.K.,Gray, N.S.
Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome.
Cell Chem Biol, 26:818-829.e9, 2019

PubMed Abstract: Covalent kinase inhibitors, which typically target cysteine residues, represent an important class of clinically relevant compounds. Approximately 215 kinases are known to have potentially targetable cysteines distributed across 18 spatially distinct locations proximal to the ATP-binding pocket. However, only 40 kinases have been covalently targeted, with certain cysteine sites being the primary focus. To address this disparity, we have developed a strategy that combines the use of a multi-targeted acrylamide-modified inhibitor, SM1-71, with a suite of complementary chemoproteomic and cellular approaches to identify additional targetable cysteines. Using this single multi-targeted compound, we successfully identified 23 kinases that are amenable to covalent inhibition including MKNK2, MAP2K1/2/3/4/6/7, GAK, AAK1, BMP2K, MAP3K7, MAPKAPK5, GSK3A/B, MAPK1/3, SRC, YES1, FGFR1, ZAK (MLTK), MAP3K1, LIMK1, and RSK2. The identification of nine of these kinases previously not targeted by a covalent inhibitor increases the number of targetable kinases and highlights opportunities for covalent kinase inhibitor development.

PubMed: 30982749
DOI: 10.1016/j.chembiol.2019.02.021

Experimental method

X-RAY DIFFRACTION (2.402 Å)