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| [[Image:1uwj.jpg|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_1uwj| PDB=1uwj | SCENE= }} | | {{STRUCTURE_1uwj| PDB=1uwj | SCENE= }} |
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| '''THE COMPLEX OF MUTANT V599E B-RAF AND BAY439006'''
| | ===THE COMPLEX OF MUTANT V599E B-RAF AND BAY439006=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_15035987}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 15035987 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_15035987}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Signal transduction]] | | [[Category: Signal transduction]] |
| [[Category: Threonine-protein kinase]] | | [[Category: Threonine-protein kinase]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 11:46:52 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 14:47:08 2008'' |