1uwh
From Proteopedia
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|PDB= 1uwh |SIZE=350|CAPTION= <scene name='initialview01'>1uwh</scene>, resolution 2.95Å | |PDB= 1uwh |SIZE=350|CAPTION= <scene name='initialview01'>1uwh</scene>, resolution 2.95Å | ||
|SITE= <scene name='pdbsite=AC1:Cl+Binding+Site+For+Chain+B'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:Cl+Binding+Site+For+Chain+B'>AC1</scene> | ||
| - | |LIGAND= | + | |LIGAND= <scene name='pdbligand=BAX:4-{4-[({[4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL]AMINO}CARBONYL)AMINO]PHENOXY}-N-METHYLPYRIDINE-2-CARBOXAMIDE'>BAX</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/ | + | |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= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1uwh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1uwh OCA], [http://www.ebi.ac.uk/pdbsum/1uwh PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1uwh RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
Over 30 mutations of the B-RAF gene associated with human cancers have been identified, the majority of which are located within the kinase domain. Here we show that of 22 B-RAF mutants analyzed, 18 have elevated kinase activity and signal to ERK in vivo. Surprisingly, three mutants have reduced kinase activity towards MEK in vitro but, by activating C-RAF in vivo, signal to ERK in cells. The structures of wild type and oncogenic V599EB-RAF kinase domains in complex with the RAF inhibitor BAY43-9006 show that the activation segment is held in an inactive conformation by association with the P loop. The clustering of most mutations to these two regions suggests that disruption of this interaction converts B-RAF into its active conformation. The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism. | Over 30 mutations of the B-RAF gene associated with human cancers have been identified, the majority of which are located within the kinase domain. Here we show that of 22 B-RAF mutants analyzed, 18 have elevated kinase activity and signal to ERK in vivo. Surprisingly, three mutants have reduced kinase activity towards MEK in vitro but, by activating C-RAF in vivo, signal to ERK in cells. The structures of wild type and oncogenic V599EB-RAF kinase domains in complex with the RAF inhibitor BAY43-9006 show that the activation segment is held in an inactive conformation by association with the P loop. The clustering of most mutations to these two regions suggests that disruption of this interaction converts B-RAF into its active conformation. The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism. | ||
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| - | ==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== | ||
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Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF., Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R, Cell. 2004 Mar 19;116(6):855-67. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15035987 15035987] | Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF., Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R, Cell. 2004 Mar 19;116(6):855-67. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15035987 15035987] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
| + | [[Category: Non-specific serine/threonine protein kinase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Transferred entry: 2 7.11 1]] | ||
[[Category: Barford, D.]] | [[Category: Barford, D.]] | ||
[[Category: Roe, S M.]] | [[Category: Roe, S M.]] | ||
[[Category: Wan, P T.C.]] | [[Category: Wan, P T.C.]] | ||
| - | [[Category: BAX]] | ||
| - | [[Category: CL]] | ||
[[Category: kinase]] | [[Category: kinase]] | ||
| - | ''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 00:16:17 2008'' |
Revision as of 21:16, 30 March 2008
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| , resolution 2.95Å | |||||||
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| Sites: | |||||||
| Ligands: | , | ||||||
| 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 | ||||||
THE COMPLEX OF WILD TYPE B-RAF AND BAY439006
Overview
Over 30 mutations of the B-RAF gene associated with human cancers have been identified, the majority of which are located within the kinase domain. Here we show that of 22 B-RAF mutants analyzed, 18 have elevated kinase activity and signal to ERK in vivo. Surprisingly, three mutants have reduced kinase activity towards MEK in vitro but, by activating C-RAF in vivo, signal to ERK in cells. The structures of wild type and oncogenic V599EB-RAF kinase domains in complex with the RAF inhibitor BAY43-9006 show that the activation segment is held in an inactive conformation by association with the P loop. The clustering of most mutations to these two regions suggests that disruption of this interaction converts B-RAF into its active conformation. The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism.
About this Structure
1UWH is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF., Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R, Cell. 2004 Mar 19;116(6):855-67. PMID:15035987
Page seeded by OCA on Mon Mar 31 00:16:17 2008
