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- PDB-6u2h: BRAF dimer bound to 14-3-3 -

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Basic information

Entry
Database: PDB / ID: 6u2h
TitleBRAF dimer bound to 14-3-3
Components
  • 14-3-3 protein zeta/delta
  • Serine/threonine-protein kinase B-raf
KeywordsSIGNALING PROTEIN/Transferase / BRAF / 14-3-3 / kinase / complex / SIGNALING PROTEIN / SIGNALING PROTEIN-Transferase complex
Function / homology
Function and homology information


Golgi reassembly / regulation of synapse maturation / NOTCH4 Activation and Transmission of Signal to the Nucleus / trehalose metabolism in response to stress / CD4-positive, alpha-beta T cell differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / establishment of Golgi localization / head morphogenesis / Signalling to p38 via RIT and RIN ...Golgi reassembly / regulation of synapse maturation / NOTCH4 Activation and Transmission of Signal to the Nucleus / trehalose metabolism in response to stress / CD4-positive, alpha-beta T cell differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / establishment of Golgi localization / head morphogenesis / Signalling to p38 via RIT and RIN / myeloid progenitor cell differentiation / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / endothelial cell apoptotic process / Rap1 signalling / negative regulation of fibroblast migration / positive regulation of glucose transmembrane transport / establishment of protein localization to membrane / negative regulation of protein localization to nucleus / mitogen-activated protein kinase kinase binding / regulation of T cell differentiation / Negative feedback regulation of MAPK pathway / KSRP (KHSRP) binds and destabilizes mRNA / GP1b-IX-V activation signalling / positive regulation of axonogenesis / Frs2-mediated activation / stress fiber assembly / positive regulation of axon regeneration / face development / synaptic vesicle exocytosis / somatic stem cell population maintenance / MAP kinase kinase activity / thyroid gland development / Regulation of localization of FOXO transcription factors / Interleukin-3, Interleukin-5 and GM-CSF signaling / MAP kinase kinase kinase activity / phosphoserine residue binding / Activation of BAD and translocation to mitochondria / cellular response to glucose starvation / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / negative regulation of endothelial cell apoptotic process / positive regulation of substrate adhesion-dependent cell spreading / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / negative regulation of TORC1 signaling / positive regulation of stress fiber assembly / response to cAMP / ERK1 and ERK2 cascade / cellular response to calcium ion / negative regulation of innate immune response / substrate adhesion-dependent cell spreading / cellular response to nerve growth factor stimulus / regulation of ERK1 and ERK2 cascade / protein sequestering activity / thymus development / long-term synaptic potentiation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / Deactivation of the beta-catenin transactivating complex / TP53 Regulates Metabolic Genes / Negative regulation of NOTCH4 signaling / animal organ morphogenesis / Spry regulation of FGF signaling / RAF activation / Signaling by high-kinase activity BRAF mutants / visual learning / MAP2K and MAPK activation / epidermal growth factor receptor signaling pathway / response to peptide hormone / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / melanosome / MAPK cascade / Signaling by BRAF and RAF1 fusions / cellular response to xenobiotic stimulus / presynapse / cell body / positive regulation of peptidyl-serine phosphorylation / T cell differentiation in thymus / regulation of cell population proliferation / T cell receptor signaling pathway / scaffold protein binding / blood microparticle / DNA-binding transcription factor binding / negative regulation of neuron apoptotic process / vesicle / transmembrane transporter binding / positive regulation of ERK1 and ERK2 cascade / non-specific serine/threonine protein kinase / neuron projection / protein kinase activity / cadherin binding / protein phosphorylation / focal adhesion / protein serine kinase activity / intracellular membrane-bounded organelle
Similarity search - Function
14-3-3 domain / Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Delta-Endotoxin; domain 1 / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. ...14-3-3 domain / Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Delta-Endotoxin; domain 1 / Diacylglycerol/phorbol-ester binding / 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-29L / Serine/threonine-protein kinase B-raf / 14-3-3 protein zeta/delta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsLiau, N.P.D. / Hymowitz, S.G. / Sudhamsu, J.
CitationJournal: Nat.Struct.Mol.Biol. / Year: 2020
Title: Negative regulation of RAF kinase activity by ATP is overcome by 14-3-3-induced dimerization.
Authors: Liau, N.P.D. / Wendorff, T.J. / Quinn, J.G. / Steffek, M. / Phung, W. / Liu, P. / Tang, J. / Irudayanathan, F.J. / Izadi, S. / Shaw, A.S. / Malek, S. / Hymowitz, S.G. / Sudhamsu, J.
History
DepositionAug 19, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 28, 2019Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2020Group: 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Feb 26, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)119,7646
Polymers119,0954
Non-polymers6692
Water37821
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8410 Å2
ΔGint-32 kcal/mol
Surface area46160 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.504, 115.752, 153.092
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 26460.891 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: YWHAZ / Production host: Escherichia coli (E. coli) / 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: 33086.852 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: Escherichia coli (E. coli)
References: UniProt: P15056, non-specific serine/threonine protein kinase
#3: Chemical ChemComp-29L / 2-{4-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridin-4-yl)-1H-pyrazol-1-yl}ethanol


Mass: 334.372 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H18N4O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 21 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.36 Å3/Da / Density % sol: 47.88 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: PEG 6000 Tris pH 7.5

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Data collection

DiffractionMean temperature: 77 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 17, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.5→34.454 Å / Num. obs: 72587 / % possible obs: 99.26 % / Redundancy: 6.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.08109 / Net I/σ(I): 13.91
Reflection shellResolution: 2.5→2.589 Å / Rmerge(I) obs: 1.718 / Mean I/σ(I) obs: 0.88 / Num. unique obs: 26121 / CC1/2: 0.528 / % possible all: 99.27

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Processing

Software
NameVersionClassification
PHENIX1.12-2829_finalrefinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4MNF, 5NAS

4mnf

5nas


Resolution: 2.5→34.454 Å / SU ML: 0.44 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 32.23 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2632 2947 4.06 %
Rwork0.2197 69640 -
obs0.2215 72587 99.37 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 216.51 Å2 / Biso mean: 95.6009 Å2 / Biso min: 38.61 Å2
Refinement stepCycle: final / Resolution: 2.5→34.454 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8090 0 50 21 8161
Biso mean--75.18 76.77 -
Num. residues----1011
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0118287
X-RAY DIFFRACTIONf_angle_d1.34511159
X-RAY DIFFRACTIONf_chiral_restr0.0861214
X-RAY DIFFRACTIONf_plane_restr0.0071431
X-RAY DIFFRACTIONf_dihedral_angle_d21.1663174
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.5-2.5410.421410.3954327397
2.541-2.58480.37661410.37063317100
2.5848-2.63180.37041420.36663328100
2.6318-2.68240.37451410.34563374100
2.6824-2.73710.35521390.33883268100
2.7371-2.79660.32581410.3234331498
2.7966-2.86170.37491440.3174327199
2.8617-2.93320.37391420.30283324100
2.9332-3.01240.31091380.29673310100
3.0124-3.1010.33591450.27933356100
3.101-3.20110.36681350.2783359100
3.2011-3.31540.32241380.2663269100
3.3154-3.4480.34281380.24823369100
3.448-3.60480.26171440.24423330100
3.6048-3.79460.24431350.2177326698
3.7946-4.0320.2341420.20943330100
4.032-4.34280.22891420.1823328100
4.3428-4.77880.21771400.1683336100
4.7788-5.46790.26311390.1872330298
5.4679-6.880.21971430.20513314100
6.88-34.4540.21681370.1644330299
Refinement TLS params.Method: refined / Origin x: 65.3088 Å / Origin y: 116.2711 Å / Origin z: -16.1859 Å
111213212223313233
T0.3638 Å20.0959 Å2-0.0189 Å2-0.39 Å20.0426 Å2--0.4755 Å2
L0.5504 °20.1525 °2-0.0448 °2-0.4319 °20.1729 °2--1.1888 °2
S-0.0133 Å °0.196 Å °0.1575 Å °-0.0694 Å °0.0224 Å °0.0629 Å °0.0921 Å °-0.0415 Å °0 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 230
2X-RAY DIFFRACTION1allB0 - 229
3X-RAY DIFFRACTION1allC448 - 733
4X-RAY DIFFRACTION1allC801
5X-RAY DIFFRACTION1allD448 - 733
6X-RAY DIFFRACTION1allD801
7X-RAY DIFFRACTION1allS1 - 31

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