This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
1uwj
From Proteopedia
| |||||||
| , resolution 3.50Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | |||||||
| Ligands: | |||||||
| Activity: | Transferred entry: 2.7.11.1, with EC number 2.7.1.37 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
THE COMPLEX OF MUTANT V599E B-RAF AND BAY439006
Contents |
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.
Disease
Known diseases associated with this structure: Adenocarcinoma of lung, somatic OMIM:[164757], Cardiofaciocutaneous syndrome OMIM:[164757], Colorectal cancer, somatic OMIM:[164757], Melanoma, melignant, somatic OMIM:[164757], Nonsmall cell lung cancer, somatic OMIM:[164757]
About this Structure
1UWJ 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 Thu Mar 20 14:37:45 2008
