9TWB

Crystal structure of BRAF(val600):MEK1(pS222) complex with asymmetric dimer interface bound to ADP

Summary for 9TWB

• Entry DOI: 10.2210/pdb9twb/pdb
• Descriptor: Dual specificity mitogen-activated protein kinase kinase 1, Serine/threonine-protein kinase B-raf, ADENOSINE-5'-DIPHOSPHATE, ... (7 entities in total)
• Functional Keywords: kinase, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 140136.70

Authors

Kondo, Y.,Notbohm, J.,Camacho, I.N.,Nagy-Davidescu, G.,Mason, T.,Muhle, J.,Standfuss, J.,Perica, T. (deposition date: 2026-01-14, release date: 2026-08-05)

Primary citation

Kondo, Y.,Notbohm, J.,Navas Camacho, I.,Nagy-Davidescu, G.,Mason, T.,Muhle, J.,Standfuss, J.,Perica, T.
Mechanism of MEK1 phosphorylation by the N-terminal acidic motif-mediated asymmetric BRAF dimer.
Mol.Cell, 2026

PubMed Abstract: The rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (RAF/MEK/ERK) signaling cascade regulates cell proliferation and differentiation and is frequently dysregulated in cancer. Approximately 90% of RAF-mutant cancers harbor mutations in B-type rapidly accelerated fibrosarcoma (BRAF). Its proto-oncogenicity is attributed to a four-residue N-terminal acidic (NtA) motif. Although a long-standing model proposes that the NtA promotes activating asymmetric RAF dimerization, the model lacks structural support. Here, we present structures of NtA-mediated asymmetric BRAF dimers bound to their substrate MEK1. Cellular and biochemical data show that the NtA is not required for KRAS-mediated BRAF recruitment to the plasma membrane but is required for the fully catalytically active state. The structure capturing BRAF in a post-catalytic state bound to Ser222-phosphorylated MEK1 further supports this model. The combination of structural and cellular data corroborates the model of NtA-driven asymmetry in BRAF activation and resolves a long-standing disconnect between RAF cancer genetics and structural biology.

PubMed: 42480522
DOI: 10.1016/j.molcel.2026.06.039

Experimental method

X-RAY DIFFRACTION (2.45 Å)