4YC8

C-Helix-Out Binding of Dasatinib Analog to c-Abl Kinase

Summary for 4YC8

• Entry DOI: 10.2210/pdb4yc8/pdb
• Related: 4YBK
• Descriptor: Tyrosine-protein kinase ABL1, 2-({6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl}amino)-N-(4-phenoxyphenyl)-1,3-thiazole-5-carboxamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: kinase, c-helix-out, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytoskeleton. Isoform IB: Nucleus membrane; Lipid-anchor: P00519
• Total number of polymer chains: 2
• Total formula weight: 68023.84

Authors

Kwarcinski, F.E.,Brandvold, K.B.,Johnson, T.J.,Phadke, S.,Meagher, J.L.,Seeliger, M.A.,Stuckey, J.A.,Soellner, M.B. (deposition date: 2015-02-19, release date: 2016-03-02, Last modification date: 2023-09-27)

Primary citation

Kwarcinski, F.E.,Brandvold, K.R.,Phadke, S.,Beleh, O.M.,Johnson, T.K.,Meagher, J.L.,Seeliger, M.A.,Stuckey, J.A.,Soellner, M.B.
Conformation-Selective Analogues of Dasatinib Reveal Insight into Kinase Inhibitor Binding and Selectivity.
Acs Chem.Biol., 11:1296-1304, 2016

PubMed Abstract: In the kinase field, there are many widely held tenets about conformation-selective inhibitors that have yet to be validated using controlled experiments. We have designed, synthesized, and characterized a series of kinase inhibitor analogues of dasatinib, an FDA-approved kinase inhibitor that binds the active conformation. This inhibitor series includes two Type II inhibitors that bind the DFG-out inactive conformation and two inhibitors that bind the αC-helix-out inactive conformation. Using this series of compounds, we analyze the impact that conformation-selective inhibitors have on target binding and kinome-wide selectivity.

PubMed: 26895387
DOI: 10.1021/acschembio.5b01018

Experimental method

X-RAY DIFFRACTION (2.9 Å)