General Information

Database Accession: DI2000028

Name: 14-3-3 zeta in complex with a diphosphorylated c-Raf peptide

PDB ID: 4ihl PDB

Experimental method: X-ray (2.20 Å)

Source organism: Homo sapiens

Proof of disorder: Inferred from motif

Kd: 2.00×10-08 M PubMed

Primary publication of the structure:

Molzan M, Kasper S, Röglin 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.
(2013) ACS Chem. Biol. :

PMID: 23808890 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.


Function and Biology Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown.

Molecular function:

identical protein binding Interacting selectively and non-covalently with an identical protein or proteins. GeneOntology

organic cyclic compound binding Interacting selectively and non-covalently with an organic cyclic compound, any molecular entity that contains carbon arranged in a cyclic molecular structure. GeneOntology

protein kinase binding Interacting selectively and non-covalently with a protein kinase, any enzyme that catalyzes the transfer of a phosphate group, usually from ATP, to a protein substrate. GeneOntology

Biological process:

signal transduction The cellular process in which a signal is conveyed to trigger a change in the activity or state of a cell. Signal transduction begins with reception of a signal (e.g. a ligand binding to a receptor or receptor activation by a stimulus such as light), or for signal transduction in the absence of ligand, signal-withdrawal or the activity of a constitutively active receptor. Signal transduction ends with regulation of a downstream cellular process, e.g. regulation of transcription or regulation of a metabolic process. Signal transduction covers signaling from receptors located on the surface of the cell and signaling via molecules located within the cell. For signaling between cells, signal transduction is restricted to events at and within the receiving cell. GeneOntology

platelet activation A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. GeneOntology

negative regulation of apoptotic process Any process that stops, prevents, or reduces the frequency, rate or extent of cell death by apoptotic process. GeneOntology

peptide transport The directed movement of peptides, compounds of two or more amino acids where the alpha carboxyl group of one is bound to the alpha amino group of another, into, out of or within a cell, or between cells, by means of some agent such as a transporter or pore. GeneOntology

regulation of gene expression Any process that modulates the frequency, rate or extent of gene expression. Gene expression is the process in which a gene's coding sequence is converted into a mature gene product or products (proteins or RNA). This includes the production of an RNA transcript as well as any processing to produce a mature RNA product or an mRNA (for protein-coding genes) and the translation of that mRNA into protein. Protein maturation is included when required to form an active form of a product from an inactive precursor form. GeneOntology

establishment of localization in cell Any process, occuring in a cell, that localizes a substance or cellular component. This may occur via movement, tethering or selective degradation. GeneOntology

organelle organization A process that is carried out at the cellular level which results in the assembly, arrangement of constituent parts, or disassembly of an organelle within a cell. An organelle is an organized structure of distinctive morphology and function. Includes the nucleus, mitochondria, plastids, vacuoles, vesicles, ribosomes and the cytoskeleton. Excludes the plasma membrane. GeneOntology

cellular component assembly The aggregation, arrangement and bonding together of a cellular component. GeneOntology

positive regulation of signal transduction Any process that activates or increases the frequency, rate or extent of signal transduction. GeneOntology

regulation of cellular component organization Any process that modulates the frequency, rate or extent of a process involved in the formation, arrangement of constituent parts, or disassembly of cell structures, including the plasma membrane and any external encapsulating structures such as the cell wall and cell envelope. GeneOntology

regulation of localization Any process that modulates the frequency, rate or extent of any process in which a cell, a substance, or a cellular entity is transported to, or maintained in, a specific location. GeneOntology

Cellular component:

mitochondrion A semiautonomous, self replicating organelle that occurs in varying numbers, shapes, and sizes in the cytoplasm of virtually all eukaryotic cells. It is notably the site of tissue respiration. GeneOntology

cytosol The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes. GeneOntology

nucleoplasm That part of the nuclear content other than the chromosomes or the nucleolus. GeneOntology

Structure Summary Structural annotations of the participating protein chains.

Entry contents: 3 distinct polypeptide molecules

Chains: P, A, B

Notes: No modifications of the original PDB file.

Chain P

Name: RAF proto-oncogene serine/threonine-protein kinase Disordered Inferred from motif

Source organism: Homo sapiens

Length: 36 residues

Sequence:Sequence according to PDB SEQRESQHRYSTPHAFTFNTSSPSSEGSLSQRQRSTSTPNVH

The sequence contains the following modified/non-standard residues:

• phosphoserine (S) at position 233 (PDB position: 233)

• phosphoserine (S) at position 259 (PDB position: 259)

UniProtKB AC: P04049 (positions: 229-264) UniProt Coverage: 5.6%

UniRef90 AC: UniRef90_P04049 (positions: 229-264) UniRef90

Chain A

Name: 14-3-3 protein zeta/delta Ordered component

Source organism: Homo sapiens

Length: 230 residues

Sequence:Sequence according to PDB SEQRESMDKNELVQKAKLAEQAERYDDMAACMKSVTEQGAELSNEERNLLSVAYKNVVGARRSSWRVVSSIEQKTEGAEKKQQMAREYREKIETELRDICNDVLSLLEKFLIPNASQAESKVFYLKMKGDYYRYLAEVAAGDDKKGIVDQSQQAYQEAFEISKKEMQPTHPIRLGLALNFSVFYYEILNSPEKACSLAKTAFDEAIAELDTLSEESYKDSTLIMQLLRDNLTLWTS

UniProtKB AC: P63104 (positions: 1-230) UniProt Coverage: 93.9%

UniRef90 AC: UniRef90_P63104 (positions: 1-230) UniRef90

Chain B

Name: 14-3-3 protein zeta/delta Ordered component

Source organism: Homo sapiens

Length: 230 residues

Sequence:Sequence according to PDB SEQRESMDKNELVQKAKLAEQAERYDDMAACMKSVTEQGAELSNEERNLLSVAYKNVVGARRSSWRVVSSIEQKTEGAEKKQQMAREYREKIETELRDICNDVLSLLEKFLIPNASQAESKVFYLKMKGDYYRYLAEVAAGDDKKGIVDQSQQAYQEAFEISKKEMQPTHPIRLGLALNFSVFYYEILNSPEKACSLAKTAFDEAIAELDTLSEESYKDSTLIMQLLRDNLTLWTS

UniProtKB AC: P63104 (positions: 1-230) UniProt Coverage: 93.9%

UniRef90 AC: UniRef90_P63104 (positions: 1-230) UniRef90

Evidence Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding.

Chain P: Disordered Inferred from motif

The protein region involved in the interaction contains two instances of a known functional linear motif (LIG_14-3-3_CanoR_1).

Chain A: Ordered component

The 14-3-3 domain involved in the interaction is known to adopt a stable structure in isolation in dimeric form (see Pfam domain PF00244). A solved structure of the domain dimer without bound ligands is represented by PDB ID 1a4o.

Chain B: Ordered component

The 14-3-3 domain involved in the interaction is known to adopt a stable structure in isolation in dimeric form (see Pfam domain PF00244). A solved structure of the domain dimer without bound ligands is represented by PDB ID 1a4o.

Related Structure(s) Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap).

There are 3 related structures in the Protein Data Bank:



Domain Type:

14-3-3







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