EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	BRAF oncogenic mutants evade autoinhibition through a common mechanism.
ジャーナル・号・ページ	Science, Vol. 388, Issue 6750, Page eadp2742, Year 2025
掲載日	2025年5月29日
著者	Hugo Lavoie / Ting Jin / Driss Lajoie / Marion Decossas / Patrick Gendron / Bing Wang / Frantisek Filandr / Malha Sahmi / Chang Hwa Jo / Sandra Weber / Geneviève Arseneault / Sasmita Tripathy / Pierre Beaulieu / Doris A Schuetz / David C Schriemer / Anne Marinier / William J Rice / Pierre Maisonneuve / Marc Therrien /
PubMed 要旨	Uncontrolled activation of the rat sarcoma (RAS)-extracellular signal-regulated kinase (ERK) pathway drives tumor growth, often because of oncogenic BRAF mutations. BRAF regulation, involving ...Uncontrolled activation of the rat sarcoma (RAS)-extracellular signal-regulated kinase (ERK) pathway drives tumor growth, often because of oncogenic BRAF mutations. BRAF regulation, involving monomeric autoinhibition and activation by dimerization, has been intensely scrutinized, but mechanisms enabling oncogenic mutants to evade regulation remain unclear. By using cryo-electron microscopy, we solved the three-dimensional structures of the three oncogenic BRAF mutant classes, including the common V600E variant. These mutations disrupted wild-type BRAF's autoinhibited state, mediated by interactions between the cysteine-rich domain and kinase domain, thereby shifting the kinase domain into a preactivated conformation. This structural change likely results from helix αC displacement. PLX8394, a BRAF inhibitor that stabilizes helix αC in an inactive conformation, restored the autoinhibited conformation of oncogenic BRAF, explaining the properties of this class of compounds.
リンク	Science / PubMed:40440367
手法	EM (単粒子)
解像度	3.06 - 5.86 Å
構造データ	43673 8vyo EMDB-43673, PDB-8vyo: Cryo-EM Structure of the BRAF WT monomer 手法: EM (単粒子) / 解像度: 3.74 Å 43674 8vyp EMDB-43674, PDB-8vyp: Cryo-EM Structure of the BRAF V600E monomer 手法: EM (単粒子) / 解像度: 3.29 Å 43675 8vyq EMDB-43675, PDB-8vyq: Cryo-EM Structure of the BRAF V600K monomer 手法: EM (単粒子) / 解像度: 4.43 Å 43676 8vyr EMDB-43676, PDB-8vyr: Cryo-EM Structure of the BRAF V600E monomer bound to GDC0879 手法: EM (単粒子) / 解像度: 4.32 Å 43677 8vys EMDB-43677, PDB-8vys: Cryo-EM Structure of the BRAF V600E monomer bound to PLX8394 手法: EM (単粒子) / 解像度: 3.06 Å 43678 8vyu EMDB-43678, PDB-8vyu: Cryo-EM Structure of the BRAF WT monomer bound to PLX8394 手法: EM (単粒子) / 解像度: 4.07 Å 43679 8vyv EMDB-43679, PDB-8vyv: Cryo-EM Structure of the BRAF K601E monomer 手法: EM (単粒子) / 解像度: 5.86 Å 43680 8vyw EMDB-43680, PDB-8vyw: Cryo-EM Structure of the BRAF D594G monomer 手法: EM (単粒子) / 解像度: 4.76 Å
化合物	ChemComp-ZN: Unknown entry ChemComp-AGS: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-γ-S / ATP-gamma-S, エネルギー貯蔵分子類似体YM PDB-1aen*: SPECIFICITY OF LIGAND BINDING TO A BURIED POLAR CAVITY AT THE ACTIVE SITE OF CYTOCHROME C PEROXIDASE (2-AMINO-5-METHYLTHIAZOLE)
由来	homo sapiens (ヒト)
キーワード	TRANSFERASE/INHIBITOR / BRAF Kinase Monomer / TRANSFERASE-INHIBITOR complex / BRAF Kinase Oncogenic Mutant Monomer / BRAF Kinase Monomer Mutant Inhibitor / BRAF Kinase Monomer Inhibitor