4JVG

B-Raf Kinase in Complex with Birb796

Summary for 4JVG

• Entry DOI: 10.2210/pdb4jvg/pdb
• Descriptor: Serine/threonine-protein kinase B-raf, 1-(5-TERT-BUTYL-2-P-TOLYL-2H-PYRAZOL-3-YL)-3-[4-(2-MORPHOLIN-4-YL-ETHOXY)-NAPHTHALEN-1-YL]-UREA (2 entities in total)
• Functional Keywords: kinase, phosphotransferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (By similarity): P15056
• Total number of polymer chains: 4
• Total formula weight: 131110.39

Authors

Lavoie, H.,Thevakumaran, N.,Gavory, G.,Li, J.,Padeganeh, A.,Guiral, S.,Duchaine, J.,Mao, D.Y.L.,Bouvier, M.,Sicheri, F.,Therrien, M. (deposition date: 2013-03-25, release date: 2013-05-29, Last modification date: 2024-02-28)

Primary citation

Lavoie, H.,Thevakumaran, N.,Gavory, G.,Li, J.J.,Padeganeh, A.,Guiral, S.,Duchaine, J.,Mao, D.Y.,Bouvier, M.,Sicheri, F.,Therrien, M.
Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization.
Nat.Chem.Biol., 9:428-436, 2013

PubMed Abstract: RAF kinases have a prominent role in cancer. Their mode of activation is complex but critically requires dimerization of their kinase domains. Unexpectedly, several ATP-competitive RAF inhibitors were recently found to promote dimerization and transactivation of RAF kinases in a RAS-dependent manner and, as a result, undesirably stimulate RAS/ERK pathway-mediated cell growth. The mechanism by which these inhibitors induce RAF kinase domain dimerization remains unclear. Here we describe bioluminescence resonance energy transfer-based biosensors for the extended RAF family that enable the detection of RAF dimerization in living cells. Notably, we demonstrate the utility of these tools for profiling kinase inhibitors that selectively modulate RAF dimerization and for probing structural determinants of RAF dimerization in vivo. Our findings, which seem generalizable to other kinase families allosterically regulated by kinase domain dimerization, suggest a model whereby ATP-competitive inhibitors mediate RAF dimerization by stabilizing a rigid closed conformation of the kinase domain.

PubMed: 23685672
DOI: 10.1038/nchembio.1257

Experimental method

X-RAY DIFFRACTION (3.09 Å)