3OMV の概要
| エントリーDOI | 10.2210/pdb3omv/pdb |
| 関連するPDBエントリー | 3D4Q |
| 分子名称 | RAF proto-oncogene serine/threonine-protein kinase, (1E)-5-(1-piperidin-4-yl-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-one oxime (2 entities in total) |
| 機能のキーワード | serine/threonine-protein kinase, transferase |
| 由来する生物種 | Homo sapiens (human) |
| 細胞内の位置 | Cytoplasm (By similarity): P04049 |
| タンパク質・核酸の鎖数 | 2 |
| 化学式量合計 | 71608.36 |
| 構造登録者 | Hatzivassiliou, G.,Song, K.,Yen, I.,Brandhuber, B.J.,Anderson, D.J.,Alvarado, R.,Ludlam, M.J.,Stokoe, D.,Gloor, S.L.,Vigers, G.P.A.,Morales, T.,Aliagas, I.,Liu, B.,Sideris, S.,Hoeflich, K.P.,Jaiswal, B.S.,Seshagiri, S.,Koeppen, H.,Belvin, M.,Friedman, L.S.,Malek, S. (登録日: 2010-08-27, 公開日: 2010-09-15, 最終更新日: 2023-09-06) |
| 主引用文献 | Hatzivassiliou, G.,Song, K.,Yen, I.,Brandhuber, B.J.,Anderson, D.J.,Alvarado, R.,Ludlam, M.J.,Stokoe, D.,Gloor, S.L.,Vigers, G.,Morales, T.,Aliagas, I.,Liu, B.,Sideris, S.,Hoeflich, K.P.,Jaiswal, B.S.,Seshagiri, S.,Koeppen, H.,Belvin, M.,Friedman, L.S.,Malek, S. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature, 464:431-435, 2010 Cited by PubMed Abstract: Activating mutations in KRAS and BRAF are found in more than 30% of all human tumours and 40% of melanoma, respectively, thus targeting this pathway could have broad therapeutic effects. Small molecule ATP-competitive RAF kinase inhibitors have potent antitumour effects on mutant BRAF(V600E) tumours but, in contrast to mitogen-activated protein kinase kinase (MEK) inhibitors, are not potent against RAS mutant tumour models, despite RAF functioning as a key effector downstream of RAS and upstream of MEK. Here we show that ATP-competitive RAF inhibitors have two opposing mechanisms of action depending on the cellular context. In BRAF(V600E) tumours, RAF inhibitors effectively block the mitogen-activated protein kinase (MAPK) signalling pathway and decrease tumour growth. Notably, in KRAS mutant and RAS/RAF wild-type tumours, RAF inhibitors activate the RAF-MEK-ERK pathway in a RAS-dependent manner, thus enhancing tumour growth in some xenograft models. Inhibitor binding activates wild-type RAF isoforms by inducing dimerization, membrane localization and interaction with RAS-GTP. These events occur independently of kinase inhibition and are, instead, linked to direct conformational effects of inhibitors on the RAF kinase domain. On the basis of these findings, we demonstrate that ATP-competitive kinase inhibitors can have opposing functions as inhibitors or activators of signalling pathways, depending on the cellular context. Furthermore, this work provides new insights into the therapeutic use of ATP-competitive RAF inhibitors. PubMed: 20130576DOI: 10.1038/nature08833 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (4 Å) |
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