1uwj: Difference between revisions
No edit summary |
No edit summary |
||
| Line 23: | Line 23: | ||
[[Category: threonine-protein kinase]] | [[Category: threonine-protein kinase]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 17:13:41 2007'' | ||
Revision as of 18:08, 5 November 2007
|
THE COMPLEX OF MUTANT V599E B-RAF AND BAY439006
OverviewOverview
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 StructureAbout this Structure
1UWJ is a Single protein structure of sequence from Homo sapiens with BAX as ligand. Active as Transferred entry: 2.7.11.1, with EC number 2.7.1.37 Structure known Active Site: AC1. Full crystallographic information is available from OCA.
ReferenceReference
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 Nov 5 17:13:41 2007