2fb8
From Proteopedia
| Line 4: | Line 4: | ||
|PDB= 2fb8 |SIZE=350|CAPTION= <scene name='initialview01'>2fb8</scene>, resolution 2.900Å | |PDB= 2fb8 |SIZE=350|CAPTION= <scene name='initialview01'>2fb8</scene>, resolution 2.900Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=215:(1Z)-5-(2-{4-[2-(DIMETHYLAMINO)ETHOXY]PHENYL}-5-PYRIDIN-4-YL-1H-IMIDAZOL-4-YL)INDAN-1-ONE OXIME'>215</scene> | + | |LIGAND= <scene name='pdbligand=215:(1Z)-5-(2-{4-[2-(DIMETHYLAMINO)ETHOXY]PHENYL}-5-PYRIDIN-4-YL-1H-IMIDAZOL-4-YL)INDAN-1-ONE+OXIME'>215</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span> |
|GENE= BRAF, BRAF1, RAFB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= BRAF, BRAF1, RAFB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2fb8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fb8 OCA], [http://www.ebi.ac.uk/pdbsum/2fb8 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2fb8 RCSB]</span> | ||
}} | }} | ||
| Line 14: | Line 17: | ||
==Overview== | ==Overview== | ||
Oncogenic BRAF alleles are both necessary and sufficient for cellular transformation, suggesting that chemical inhibition of the activated mutant protein kinase may reverse the tumor phenotype. Here, we report the characterization of SB-590885, a novel triarylimidazole that selectively inhibits Raf kinases with more potency towards B-Raf than c-Raf. Crystallographic analysis revealed that SB-590885 stabilizes the oncogenic B-Raf kinase domain in an active configuration, which is distinct from the previously reported mechanism of action of the multi-kinase inhibitor, BAY43-9006. Malignant cells expressing oncogenic B-Raf show selective inhibition of mitogen-activated protein kinase activation, proliferation, transformation, and tumorigenicity when exposed to SB-590885, whereas other cancer cell lines and normal cells display variable sensitivities or resistance to similar treatment. These studies support the validation of oncogenic B-Raf as a target for cancer therapy and provide the first evidence of a correlation between the expression of oncogenic BRAF alleles and a positive response to a selective B-Raf inhibitor. | Oncogenic BRAF alleles are both necessary and sufficient for cellular transformation, suggesting that chemical inhibition of the activated mutant protein kinase may reverse the tumor phenotype. Here, we report the characterization of SB-590885, a novel triarylimidazole that selectively inhibits Raf kinases with more potency towards B-Raf than c-Raf. Crystallographic analysis revealed that SB-590885 stabilizes the oncogenic B-Raf kinase domain in an active configuration, which is distinct from the previously reported mechanism of action of the multi-kinase inhibitor, BAY43-9006. Malignant cells expressing oncogenic B-Raf show selective inhibition of mitogen-activated protein kinase activation, proliferation, transformation, and tumorigenicity when exposed to SB-590885, whereas other cancer cell lines and normal cells display variable sensitivities or resistance to similar treatment. These studies support the validation of oncogenic B-Raf as a target for cancer therapy and provide the first evidence of a correlation between the expression of oncogenic BRAF alleles and a positive response to a selective B-Raf inhibitor. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Adenocarcinoma of lung, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164757 164757]], Cardiofaciocutaneous syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164757 164757]], Colorectal cancer, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164757 164757]], Melanoma, melignant, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164757 164757]], Nonsmall cell lung cancer, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164757 164757]] | ||
==About this Structure== | ==About this Structure== | ||
| Line 30: | Line 30: | ||
[[Category: Lougheed, J C.]] | [[Category: Lougheed, J C.]] | ||
[[Category: Stout, T J.]] | [[Category: Stout, T J.]] | ||
| - | [[Category: 215]] | ||
[[Category: kinase domain]] | [[Category: kinase domain]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:00:24 2008'' |
Revision as of 00:00, 31 March 2008
| |||||||
| , resolution 2.900Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Gene: | BRAF, BRAF1, RAFB1 (Homo sapiens) | ||||||
| Activity: | Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Structure of the B-Raf kinase domain bound to SB-590885
Overview
Oncogenic BRAF alleles are both necessary and sufficient for cellular transformation, suggesting that chemical inhibition of the activated mutant protein kinase may reverse the tumor phenotype. Here, we report the characterization of SB-590885, a novel triarylimidazole that selectively inhibits Raf kinases with more potency towards B-Raf than c-Raf. Crystallographic analysis revealed that SB-590885 stabilizes the oncogenic B-Raf kinase domain in an active configuration, which is distinct from the previously reported mechanism of action of the multi-kinase inhibitor, BAY43-9006. Malignant cells expressing oncogenic B-Raf show selective inhibition of mitogen-activated protein kinase activation, proliferation, transformation, and tumorigenicity when exposed to SB-590885, whereas other cancer cell lines and normal cells display variable sensitivities or resistance to similar treatment. These studies support the validation of oncogenic B-Raf as a target for cancer therapy and provide the first evidence of a correlation between the expression of oncogenic BRAF alleles and a positive response to a selective B-Raf inhibitor.
About this Structure
2FB8 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885., King AJ, Patrick DR, Batorsky RS, Ho ML, Do HT, Zhang SY, Kumar R, Rusnak DW, Takle AK, Wilson DM, Hugger E, Wang L, Karreth F, Lougheed JC, Lee J, Chau D, Stout TJ, May EW, Rominger CM, Schaber MD, Luo L, Lakdawala AS, Adams JL, Contractor RG, Smalley KS, Herlyn M, Morrissey MM, Tuveson DA, Huang PS, Cancer Res. 2006 Dec 1;66(23):11100-5. PMID:17145850
Page seeded by OCA on Mon Mar 31 03:00:24 2008
