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- PDB-7mff: Dimeric (BRAF)2:(14-3-3)2 complex bound to SB590885 Inhibitor -

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Basic information

Entry
Database: PDB / ID: 7mff
TitleDimeric (BRAF)2:(14-3-3)2 complex bound to SB590885 Inhibitor
Components
  • 14-3-3 protein zeta/delta
  • Serine/threonine-protein kinase B-raf
KeywordsSIGNALING PROTEIN / B-Raf / 14-3-3 / B-Raf complex / B-Raf dimer / Active B-Raf / SB590885 / Serine/threonine-protein kinase B-raf
Function / homology
Function and homology information


synaptic target recognition / Golgi reassembly / CD4-positive, alpha-beta T cell differentiation / NOTCH4 Activation and Transmission of Signal to the Nucleus / positive regulation of axon regeneration / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / establishment of Golgi localization / Signalling to p38 via RIT and RIN / respiratory system process ...synaptic target recognition / Golgi reassembly / CD4-positive, alpha-beta T cell differentiation / NOTCH4 Activation and Transmission of Signal to the Nucleus / positive regulation of axon regeneration / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / establishment of Golgi localization / Signalling to p38 via RIT and RIN / respiratory system process / head morphogenesis / ARMS-mediated activation / myeloid progenitor cell differentiation / tube formation / endothelial cell apoptotic process / regulation of synapse maturation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling / negative regulation of fibroblast migration / positive regulation of D-glucose transmembrane transport / establishment of protein localization to membrane / regulation of T cell differentiation / negative regulation of protein localization to nucleus / positive regulation of axonogenesis / KSRP (KHSRP) binds and destabilizes mRNA / Negative feedback regulation of MAPK pathway / GP1b-IX-V activation signalling / Frs2-mediated activation / stress fiber assembly / face development / MAP kinase kinase activity / thyroid gland development / Regulation of localization of FOXO transcription factors / Interleukin-3, Interleukin-5 and GM-CSF signaling / somatic stem cell population maintenance / synaptic vesicle exocytosis / positive regulation of peptidyl-serine phosphorylation / Activation of BAD and translocation to mitochondria / phosphoserine residue binding / MAP kinase kinase kinase activity / negative regulation of endothelial cell apoptotic process / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / regulation of ERK1 and ERK2 cascade / postsynaptic modulation of chemical synaptic transmission / protein targeting / cellular response to glucose starvation / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / ERK1 and ERK2 cascade / positive regulation of stress fiber assembly / negative regulation of TORC1 signaling / positive regulation of substrate adhesion-dependent cell spreading / Transcriptional and post-translational regulation of MITF-M expression and activity / substrate adhesion-dependent cell spreading / lung development / negative regulation of innate immune response / cellular response to calcium ion / thymus development / animal organ morphogenesis / hippocampal mossy fiber to CA3 synapse / TP53 Regulates Metabolic Genes / Translocation of SLC2A4 (GLUT4) to the plasma membrane / sperm end piece / Deactivation of the beta-catenin transactivating complex / protein sequestering activity / regulation of protein stability / RAF activation / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / Negative regulation of NOTCH4 signaling / MAP2K and MAPK activation / visual learning / cellular response to xenobiotic stimulus / centriolar satellite / epidermal growth factor receptor signaling pathway / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Signaling by BRAF and RAF1 fusions / melanosome / intracellular protein localization / long-term synaptic potentiation / T cell differentiation in thymus / MAPK cascade / regulation of cell population proliferation / T cell receptor signaling pathway / sperm principal piece / presynapse / cell body / sperm midpiece / angiogenesis / scaffold protein binding / protein phosphatase binding / blood microparticle / DNA-binding transcription factor binding / vesicle
Similarity search - Function
Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / 14-3-3 domain / Delta-Endotoxin; domain 1 / Phorbol esters/diacylglycerol binding domain (C1 domain) / : / Zinc finger phorbol-ester/DAG-type signature. ...Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / 14-3-3 domain / Delta-Endotoxin; domain 1 / Phorbol esters/diacylglycerol binding domain (C1 domain) / : / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily / 14-3-3 proteins signature 2. / 14-3-3 protein, conserved site / 14-3-3 proteins signature 1. / 14-3-3 protein / 14-3-3 homologues / 14-3-3 domain / 14-3-3 domain superfamily / 14-3-3 protein / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ubiquitin-like domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-215 / Serine/threonine-protein kinase B-raf / 14-3-3 protein zeta/delta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.89 Å
AuthorsMartinez Fiesco, J.A. / Ping, Z. / Durrant, D.E. / Morrison, D.K.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)ZIA BC 011744 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)ZIA BC 010329 United States
CitationJournal: Nat Commun / Year: 2022
Title: Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding.
Authors: Juliana A Martinez Fiesco / David E Durrant / Deborah K Morrison / Ping Zhang /
Abstract: RAF kinases are essential effectors of RAS, but how RAS binding initiates the conformational changes needed for autoinhibited RAF monomers to form active dimers has remained unclear. Here, we present ...RAF kinases are essential effectors of RAS, but how RAS binding initiates the conformational changes needed for autoinhibited RAF monomers to form active dimers has remained unclear. Here, we present cryo-electron microscopy structures of full-length BRAF complexes derived from mammalian cells: autoinhibited, monomeric BRAF:14-3-3:MEK and BRAF:14-3-3 complexes, and an inhibitor-bound, dimeric BRAF:14-3-3 complex, at 3.7, 4.1, and 3.9 Å resolution, respectively. In both autoinhibited, monomeric structures, the RAS binding domain (RBD) of BRAF is resolved, revealing that the RBD forms an extensive contact interface with the 14-3-3 protomer bound to the BRAF C-terminal site and that key basic residues required for RBD-RAS binding are exposed. Moreover, through structure-guided mutational studies, our findings indicate that RAS-RAF binding is a dynamic process and that RBD residues at the center of the RBD:14-3-3 interface have a dual function, first contributing to RAF autoinhibition and then to the full spectrum of RAS-RBD interactions.
History
DepositionApr 9, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 26, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Nov 20, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
C: 14-3-3 protein zeta/delta
D: 14-3-3 protein zeta/delta
A: Serine/threonine-protein kinase B-raf
B: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)225,8576
Polymers224,9504
Non-polymers9072
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein 14-3-3 protein zeta/delta / Protein kinase C inhibitor protein 1 / KCIP-1


Mass: 27777.092 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) / References: UniProt: P63104
#2: Protein Serine/threonine-protein kinase B-raf / Proto-oncogene B-Raf / p94 / v-Raf murine sarcoma viral oncogene homolog B1


Mass: 84697.695 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Homo sapiens (human)
References: UniProt: P15056, non-specific serine/threonine protein kinase
#3: Chemical ChemComp-215 / (1Z)-5-(2-{4-[2-(DIMETHYLAMINO)ETHOXY]PHENYL}-5-PYRIDIN-4-YL-1H-IMIDAZOL-4-YL)INDAN-1-ONE OXIME


Mass: 453.536 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H27N5O2
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Active dimeric (B-Raf)2:(14-3-3)2 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Buffer component
IDConc.NameBuffer-ID
120 mMTris1
2200 mMNaCl1
310 mMDTT1
SpecimenConc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 57 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.89 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 203343 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0028154
ELECTRON MICROSCOPYf_angle_d0.49311008
ELECTRON MICROSCOPYf_dihedral_angle_d4.4121158
ELECTRON MICROSCOPYf_chiral_restr0.0381218
ELECTRON MICROSCOPYf_plane_restr0.0041461

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