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PDBsum entry 3hec
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References listed in PDB file
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Key reference
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Title
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Analysis of imatinib and sorafenib binding to p38alpha compared with c-Abl and b-Raf provides structural insights for understanding the selectivity of inhibitors targeting the dfg-Out form of protein kinases.
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Authors
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H.V.Namboodiri,
M.Bukhtiyarova,
J.Ramcharan,
M.Karpusas,
Y.Lee,
E.B.Springman.
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Ref.
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Biochemistry, 2010,
49,
3611-3618.
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PubMed id
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Abstract
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Protein kinases c-Abl, b-Raf, and p38alpha are recognized as important targets
for therapeutic intervention. c-Abl and b-Raf are major targets of marketed
oncology drugs Imatinib (Gleevec) and Sorafenib (Nexavar), respectively, and
BIRB-796 is a p38alpha inhibitor that reached Phase II clinical trials. A shared
feature of these drugs is the fact that they bind to the DFG-out forms of their
kinase targets. Although the discovery of this class of kinase inhibitors has
increased the level of emphasis on the design of DFG-out inhibitors, the
structural determinants for their binding and stabilization of the DFG-out
conformation remain unclear. To improve our understanding of these determinants,
we determined cocrystal structures of Imatinib and Sorafenib with p38alpha. We
also conducted a detailed analysis of Imatinib and Sorafenib binding to p38alpha
in comparison with BIRB-796, including binding kinetics, binding interactions,
the solvent accessible surface area (SASA) of the ligands, and stabilization of
key structural elements of the protein upon ligand binding. Our results yield an
improved understanding of the structural requirements for stabilizing the
DFG-out form and a rationale for understanding the genesis of ligand selectivity
among DFG-out inhibitors of protein kinases.
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