1UWH

The complex of wild type B-RAF and BAY439006.

1UWH の概要

• エントリーDOI: 10.2210/pdb1uwh/pdb
• 関連するPDBエントリー: 1UWJ
• 分子名称: B-RAF PROTO-ONCOGENE SERINE/THREONINE-PROTEIN KINASE, 4-{4-[({[4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL]AMINO}CARBONYL)AMINO]PHENOXY}-N-METHYLPYRIDINE-2-CARBOXAMIDE, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: transferase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Nucleus : P15056
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 63809.92

構造登録者

Barford, D.,Roe, S.M.,Wan, P.T.C.,Cancer Genome Project (登録日: 2004-02-05, 公開日: 2004-03-19, 最終更新日: 2023-12-13)

主引用文献

Wan, P.T.C.,Garnett, M.J.,Roe, S.M.,Lee, S.,Niculescu-Duvaz, D.,Good, V.M.,Jones, C.M.,Marshall, C.J.,Springer, C.J.,Barford, D.,Marais, R.
Mechanism of Activation of the Raf-Erk Signaling Pathway by Oncogenic Mutations of B-Raf
Cell(Cambridge,Mass.), 116:855-, 2004

PubMed Abstract: 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.

PubMed: 15035987
DOI: 10.1016/S0092-8674(04)00215-6

実験手法

X-RAY DIFFRACTION (2.95 Å)