6NYB

Structure of a MAPK pathway complex

6NYB の概要

• エントリーDOI: 10.2210/pdb6nyb/pdb
• EMDBエントリー: 0541
• 分子名称: Serine/threonine-protein kinase B-raf, Dual specificity mitogen-activated protein kinase kinase 1, 14-3-3 protein zeta, ... (8 entities in total)
• 機能のキーワード: transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 193116.14

構造登録者

Park, E.,Rawson, S.,Li, K.,Jeon, H.,Eck, M.J. (登録日: 2019-02-11, 公開日: 2019-10-09, 最終更新日: 2025-05-14)

主引用文献

Park, E.,Rawson, S.,Li, K.,Kim, B.W.,Ficarro, S.B.,Pino, G.G.,Sharif, H.,Marto, J.A.,Jeon, H.,Eck, M.J.
Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes.
Nature, 575:545-550, 2019

PubMed Abstract: RAF family kinases are RAS-activated switches that initiate signalling through the MAP kinase cascade to control cellular proliferation, differentiation and survival. RAF activity is tightly regulated and inappropriate activation is a frequent cause of cancer; however, the structural basis for RAF regulation is poorly understood at present. Here we use cryo-electron microscopy to determine autoinhibited and active-state structures of full-length BRAF in complexes with MEK1 and a 14-3-3 dimer. The reconstruction reveals an inactive BRAF-MEK1 complex restrained in a cradle formed by the 14-3-3 dimer, which binds the phosphorylated S365 and S729 sites that flank the BRAF kinase domain. The BRAF cysteine-rich domain occupies a central position that stabilizes this assembly, but the adjacent RAS-binding domain is poorly ordered and peripheral. The 14-3-3 cradle maintains autoinhibition by sequestering the membrane-binding cysteine-rich domain and blocking dimerization of the BRAF kinase domain. In the active state, these inhibitory interactions are released and a single 14-3-3 dimer rearranges to bridge the C-terminal pS729 binding sites of two BRAFs, which drives the formation of an active, back-to-back BRAF dimer. Our structural snapshots provide a foundation for understanding normal RAF regulation and its mutational disruption in cancer and developmental syndromes.

PubMed: 31581174
DOI: 10.1038/s41586-019-1660-y

実験手法

ELECTRON MICROSCOPY (4.1 Å)