3OMV

Crystal structure of c-raf (raf-1)

Replaces:  3LB7

Summary for 3OMV

• Entry DOI: 10.2210/pdb3omv/pdb
• Related: 3D4Q
• Descriptor: 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)
• Functional Keywords: serine/threonine-protein kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm (By similarity): P04049
• Total number of polymer chains: 2
• Total formula weight: 71608.36

Authors

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. (deposition date: 2010-08-27, release date: 2010-09-15, Last modification date: 2023-09-06)

Primary citation

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

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: 20130576
DOI: 10.1038/nature08833

Experimental method

X-RAY DIFFRACTION (4 Å)