6U2H

BRAF dimer bound to 14-3-3

Summary for 6U2H

• Entry DOI: 10.2210/pdb6u2h/pdb
• Related: 6U2G
• Descriptor: 14-3-3 protein zeta/delta, Serine/threonine-protein kinase B-raf, 2-{4-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridin-4-yl)-1H-pyrazol-1-yl}ethanol, ... (4 entities in total)
• Functional Keywords: braf, 14-3-3, kinase, complex, signaling protein, signaling protein-transferase complex, signaling protein/transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 119764.23

Authors

Liau, N.P.D.,Hymowitz, S.G.,Sudhamsu, J. (deposition date: 2019-08-19, release date: 2019-08-28, Last modification date: 2024-11-06)

Primary citation

Liau, N.P.D.,Wendorff, T.J.,Quinn, J.G.,Steffek, M.,Phung, W.,Liu, P.,Tang, J.,Irudayanathan, F.J.,Izadi, S.,Shaw, A.S.,Malek, S.,Hymowitz, S.G.,Sudhamsu, J.
Negative regulation of RAF kinase activity by ATP is overcome by 14-3-3-induced dimerization.
Nat.Struct.Mol.Biol., 27:134-141, 2020

PubMed Abstract: The RAS-RAF-MEK-ERK signaling axis is frequently activated in human cancers. Physiological concentrations of ATP prevent formation of RAF kinase-domain (RAF) dimers that are critical for activity. Here we present a 2.9-Å-resolution crystal structure of human BRAF in complex with MEK and the ATP analog AMP-PCP, revealing interactions between BRAF and ATP that induce an inactive, monomeric conformation of BRAF. We also determine how 14-3-3 relieves the negative regulatory effect of ATP through a 2.5-Å-resolution crystal structure of the BRAF-14-3-3 complex, in which dimeric 14-3-3 enforces a dimeric BRAF assembly to increase BRAF activity. Our data suggest that most oncogenic BRAF mutations alter interactions with ATP and counteract the negative effects of ATP binding by lowering the threshold for RAF dimerization and pathway activation. Our study establishes a framework for rationalizing oncogenic BRAF mutations and provides new avenues for improved RAF-inhibitor discovery.

PubMed: 31988522
DOI: 10.1038/s41594-019-0365-0

Experimental method

X-RAY DIFFRACTION (2.5 Å)