| dc.contributor.author |
Namboodiri, HV |
en |
| dc.contributor.author |
Bukhtiyarova, M |
en |
| dc.contributor.author |
Ramcharan, J |
en |
| dc.contributor.author |
Karpusas, M |
en |
| dc.contributor.author |
Lee, Y |
en |
| dc.contributor.author |
Springman, EB |
en |
| dc.date.accessioned |
2014-06-06T06:50:47Z |
|
| dc.date.available |
2014-06-06T06:50:47Z |
|
| dc.date.issued |
2010 |
en |
| dc.identifier.issn |
00062960 |
en |
| dc.identifier.uri |
http://dx.doi.org/10.1021/bi100070r |
en |
| dc.identifier.uri |
http://62.217.125.90/xmlui/handle/123456789/5160 |
|
| dc.subject.other |
Binding interaction |
en |
| dc.subject.other |
Binding kinetics |
en |
| dc.subject.other |
Clinical trial |
en |
| dc.subject.other |
Cocrystal structure |
en |
| dc.subject.other |
Gleevec |
en |
| dc.subject.other |
Imatinib |
en |
| dc.subject.other |
Kinase inhibitors |
en |
| dc.subject.other |
Kinase targets |
en |
| dc.subject.other |
Ligand binding |
en |
| dc.subject.other |
Phase II |
en |
| dc.subject.other |
Protein kinase |
en |
| dc.subject.other |
Protein kinases c |
en |
| dc.subject.other |
Solvent accessible surface areas |
en |
| dc.subject.other |
Sorafenib |
en |
| dc.subject.other |
Structural determinants |
en |
| dc.subject.other |
Structural elements |
en |
| dc.subject.other |
Structural insights |
en |
| dc.subject.other |
Structural requirements |
en |
| dc.subject.other |
Therapeutic intervention |
en |
| dc.subject.other |
Binding energy |
en |
| dc.subject.other |
Ligands |
en |
| dc.subject.other |
Stabilization |
en |
| dc.subject.other |
Targets |
en |
| dc.subject.other |
Proteins |
en |
| dc.subject.other |
Abelson kinase |
en |
| dc.subject.other |
aspartylphenylalanylglycine |
en |
| dc.subject.other |
B Raf kinase |
en |
| dc.subject.other |
doramapimod |
en |
| dc.subject.other |
glycine derivative |
en |
| dc.subject.other |
imatinib |
en |
| dc.subject.other |
ligand |
en |
| dc.subject.other |
mitogen activated protein kinase 14 |
en |
| dc.subject.other |
protein |
en |
| dc.subject.other |
protein kinase |
en |
| dc.subject.other |
protein kinase inhibitor |
en |
| dc.subject.other |
solvent |
en |
| dc.subject.other |
sorafenib |
en |
| dc.subject.other |
unclassified drug |
en |
| dc.subject.other |
article |
en |
| dc.subject.other |
binding kinetics |
en |
| dc.subject.other |
controlled study |
en |
| dc.subject.other |
crystal structure |
en |
| dc.subject.other |
drug protein binding |
en |
| dc.subject.other |
drug selectivity |
en |
| dc.subject.other |
drug targeting |
en |
| dc.subject.other |
ligand binding |
en |
| dc.subject.other |
nonhuman |
en |
| dc.subject.other |
priority journal |
en |
| dc.subject.other |
protein conformation |
en |
| dc.subject.other |
protein stability |
en |
| dc.subject.other |
protein structure |
en |
| dc.subject.other |
structure activity relation |
en |
| dc.subject.other |
Benzenesulfonates |
en |
| dc.subject.other |
Crystallography, X-Ray |
en |
| dc.subject.other |
Humans |
en |
| dc.subject.other |
Mitogen-Activated Protein Kinase 14 |
en |
| dc.subject.other |
Models, Molecular |
en |
| dc.subject.other |
Molecular Structure |
en |
| dc.subject.other |
Naphthalenes |
en |
| dc.subject.other |
Piperazines |
en |
| dc.subject.other |
Protein Binding |
en |
| dc.subject.other |
Protein Kinase Inhibitors |
en |
| dc.subject.other |
Proto-Oncogene Proteins B-raf |
en |
| dc.subject.other |
Proto-Oncogene Proteins c-abl |
en |
| dc.subject.other |
Pyrazoles |
en |
| dc.subject.other |
Pyridines |
en |
| dc.subject.other |
Pyrimidines |
en |
| dc.subject.other |
Structure-Activity Relationship |
en |
| dc.title |
Analysis of imatinib and sorafenib binding to p38α Compared with c-Abl and b-Raf provides structural insights for understanding the selectivity of inhibitors targeting the DFG-out form of protein kinases |
en |
| heal.type |
journalArticle |
en |
| heal.identifier.primary |
10.1021/bi100070r |
en |
| heal.publicationDate |
2010 |
en |
| heal.abstract |
Protein kinases c-Abl, b-Raf, and p38α 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 p38α 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 p38α. We also conducted a detailed analysis of Imatinib and Sorafenib binding to p38α 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. © 2010 American Chemical Society. |
en |
| heal.journalName |
Biochemistry |
en |
| dc.identifier.issue |
17 |
en |
| dc.identifier.volume |
49 |
en |
| dc.identifier.doi |
10.1021/bi100070r |
en |
| dc.identifier.spage |
3611 |
en |
| dc.identifier.epage |
3618 |
en |