1uwh
From Proteopedia
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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 . | + | 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== | ==About this Structure== | ||
| - | 1UWH is a | + | 1UWH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CL and BAX as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1UWH OCA]. |
==Reference== | ==Reference== | ||
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[[Category: kinase]] | [[Category: kinase]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 12:54:44 2007'' |
Revision as of 10:49, 5 November 2007
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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 with CL and BAX as ligands. 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.
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
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