4IEA: 14-3-3 Isoform Sigma In Complex With A Phosphorylated C-raf Peptide

Citation:
Abstract
One-third of all human cancers harbor somatic RAS mutations. This leads to aberrant activation of downstream signaling pathways involving the RAF kinases. Current ATP-competitive RAF inhibitors are active in cancers with somatic RAF mutations, such as BRAF(V600) mutant melanomas. However, they paradoxically promote the growth of RAS mutant tumors, partly due to the complex interplay between different homo- and heterodimers of A-RAF, B-RAF, and C-RAF. Based on pathway analysis and structure-guided compound identification, we describe the natural product cotylenin-A (CN-A) as stabilizer of the physical interaction of C-RAF with 14-3-3 proteins. CN-A binds to inhibitory 14-3-3 interaction sites of C-RAF, pSer233, and pSer259, but not to the activating interaction site, pSer621. While CN-A alone is inactive in RAS mutant cancer models, combined treatment with CN-A and an anti-EGFR antibody synergistically suppresses tumor growth in vitro and in vivo. This defines a novel pharmacologic strategy for treatment of RAS mutant cancers.
PDB ID: 4IEADownload
MMDB ID: 113718
PDB Deposition Date: 2012/12/13
Updated in MMDB: 2013/10
Experimental Method:
x-ray diffraction
Resolution: 1.7  Å
Source Organism:
Similar Structures:
Biological Unit for 4IEA: tetrameric; determined by author and by software (PISA)
Molecular Components in 4IEA
Label Count Molecule
Proteins (4 molecules)
2
14-3-3 Protein Sigma(Gene symbol: SFN)
Molecule annotation
2
RAF Proto-oncogene Serine/threonine-protein Kinase(Gene symbol: RAF1)
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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