4MNF

Crystal structure of BRAF-V600E bound to GDC0879

Summary for 4MNF

• Entry DOI: 10.2210/pdb4mnf/pdb
• Related: 4MNE
• Descriptor: 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, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: raf, mapk, kinase domain, atp-binding, erk, ras, pak, active conformation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (By similarity): P15056
• Total number of polymer chains: 2
• Total formula weight: 75286.02

Authors

Sudhamsu, J.,Haling, J.R.,Morales, T.,Brandhuber, B.,Hymowitz, S.G. (deposition date: 2013-09-10, release date: 2014-06-18, Last modification date: 2023-09-20)

Primary citation

Haling, J.R.,Sudhamsu, J.,Yen, I.,Sideris, S.,Sandoval, W.,Phung, W.,Bravo, B.J.,Giannetti, A.M.,Peck, A.,Masselot, A.,Morales, T.,Smith, D.,Brandhuber, B.J.,Hymowitz, S.G.,Malek, S.
Structure of the BRAF-MEK Complex Reveals a Kinase Activity Independent Role for BRAF in MAPK Signaling.
Cancer Cell, 26:402-413, 2014

PubMed Abstract: Numerous oncogenic mutations occur within the BRAF kinase domain (BRAF(KD)). Here we show that stable BRAF-MEK1 complexes are enriched in BRAF(WT) and KRAS mutant (MT) cells but not in BRAF(MT) cells. The crystal structure of the BRAF(KD) in a complex with MEK1 reveals a face-to-face dimer sensitive to MEK1 phosphorylation but insensitive to BRAF dimerization. Structure-guided studies reveal that oncogenic BRAF mutations function by bypassing the requirement for BRAF dimerization for activity or weakening the interaction with MEK1. Finally, we show that conformation-specific BRAF inhibitors can sequester a dormant BRAF-MEK1 complex resulting in pathway inhibition. Taken together, these findings reveal a regulatory role for BRAF in the MAPK pathway independent of its kinase activity but dependent on interaction with MEK.

PubMed: 25155755
DOI: 10.1016/j.ccr.2014.07.007

Experimental method

X-RAY DIFFRACTION (2.802 Å)