4IHL

Human 14-3-3 isoform zeta in complex with a diphoyphorylated C-RAF peptide and Cotylenin A

Summary for 4IHL

• Entry DOI: 10.2210/pdb4ihl/pdb
• Related: 1A4O 1IB1 1QJA 1QJB 3E6Y 3SMK 4FJ3 4IEA
• Descriptor: 14-3-3 protein zeta/delta, RAF proto-oncogene serine/threonine-protein kinase, POTASSIUM ION, ... (5 entities in total)
• Functional Keywords: 14-3-3 fold, raf, all alpha-helical, adapter protein, protein-protein interaction, peptide binding protein
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P63104 P04049
• Total number of polymer chains: 3
• Total formula weight: 58948.32

Authors

Molzan, M.,Ottmann, C. (deposition date: 2012-12-19, release date: 2013-09-25, Last modification date: 2024-10-09)

Primary citation

Molzan, M.,Kasper, S.,Roglin, L.,Skwarczynska, M.,Sassa, T.,Inoue, T.,Breitenbuecher, F.,Ohkanda, J.,Kato, N.,Schuler, M.,Ottmann, C.
Stabilization of Physical RAF/14-3-3 Interaction by Cotylenin A as Treatment Strategy for RAS Mutant Cancers.
Acs Chem.Biol., 8:1869-1875, 2013

PubMed 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.

PubMed: 23808890
DOI: 10.1021/cb4003464

Experimental method

X-RAY DIFFRACTION (2.2 Å)