4JVG

B-Raf Kinase in Complex with Birb796

4JVG の概要

• エントリーDOI: 10.2210/pdb4jvg/pdb
• 分子名称: 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)
• 機能のキーワード: kinase, phosphotransferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus (By similarity): P15056
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 131110.39

構造登録者

Lavoie, H.,Thevakumaran, N.,Gavory, G.,Li, J.,Padeganeh, A.,Guiral, S.,Duchaine, J.,Mao, D.Y.L.,Bouvier, M.,Sicheri, F.,Therrien, M. (登録日: 2013-03-25, 公開日: 2013-05-29, 最終更新日: 2024-02-28)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.09 Å)