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- EMDB-23815: Dimeric (BRAF)2:(14-3-3)2 complex bound to SB590885 Inhibitor -

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Basic information

Entry
Database: EMDB / ID: EMD-23815
TitleDimeric (BRAF)2:(14-3-3)2 complex bound to SB590885 Inhibitor
Map dataDimeric (B-Raf)2:(14-3-3)2 complex bound to SB590885 Inhibitor
Sample
  • Complex: Active dimeric (B-Raf)2:(14-3-3)2 complex
    • Protein or peptide: 14-3-3 protein zeta/delta
    • Protein or peptide: Serine/threonine-protein kinase B-raf
  • Ligand: (1Z)-5-(2-{4-[2-(DIMETHYLAMINO)ETHOXY]PHENYL}-5-PYRIDIN-4-YL-1H-IMIDAZOL-4-YL)INDAN-1-ONE OXIME
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 / protein sequestering activity / cellular response to nerve growth factor stimulus / regulation of ERK1 and ERK2 cascade / 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
Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / 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 ...Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / 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
Similarity search - Domain/homology
Serine/threonine-protein kinase B-raf / 14-3-3 protein zeta/delta
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.89 Å
AuthorsMartinez Fiesco JA / Ping Z / Durrant DE / Morrison DK
Funding support United States, 2 items
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, 2021-
Header (metadata) releaseJan 26, 2022-
Map releaseJan 26, 2022-
UpdateFeb 9, 2022-
Current statusFeb 9, 2022Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.049
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.049
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7mff
  • Surface level: 0.049
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23815.png

Downloads & links

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Map

FileDownload / File: emd_23815.map.gz / Format: CCP4 / Size: 8.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationDimeric (B-Raf)2:(14-3-3)2 complex bound to SB590885 Inhibitor
Voxel sizeX=Y=Z: 1.348 Å
Density
Contour LevelBy AUTHOR: 0.049 / Movie #1: 0.049
Minimum - Maximum-0.20007819 - 0.31258443
Average (Standard dev.)0.00075961766 (±0.00957075)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions130130130
Spacing130130130
CellA=B=C: 175.24 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.3481.3481.348
M x/y/z130130130
origin x/y/z0.0000.0000.000
length x/y/z175.240175.240175.240
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS130130130
D min/max/mean-0.2000.3130.001

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Supplemental data

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Sample components

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Entire : Active dimeric (B-Raf)2:(14-3-3)2 complex

EntireName: Active dimeric (B-Raf)2:(14-3-3)2 complex
Components
  • Complex: Active dimeric (B-Raf)2:(14-3-3)2 complex
    • Protein or peptide: 14-3-3 protein zeta/delta
    • Protein or peptide: Serine/threonine-protein kinase B-raf
  • Ligand: (1Z)-5-(2-{4-[2-(DIMETHYLAMINO)ETHOXY]PHENYL}-5-PYRIDIN-4-YL-1H-IMIDAZOL-4-YL)INDAN-1-ONE OXIME

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Supramolecule #1: Active dimeric (B-Raf)2:(14-3-3)2 complex

SupramoleculeName: Active dimeric (B-Raf)2:(14-3-3)2 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: 14-3-3 protein zeta/delta

MacromoleculeName: 14-3-3 protein zeta/delta / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 27.777092 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDKNELVQKA KLAEQAERYD DMAACMKSVT EQGAELSNEE RNLLSVAYKN VVGARRSSWR VVSSIEQKTE GAEKKQQMAR EYREKIETE LRDICNDVLS LLEKFLIPNA SQAESKVFYL KMKGDYYRYL AEVAAGDDKK GIVDQSQQAY QEAFEISKKE M QPTHPIRL ...String:
MDKNELVQKA KLAEQAERYD DMAACMKSVT EQGAELSNEE RNLLSVAYKN VVGARRSSWR VVSSIEQKTE GAEKKQQMAR EYREKIETE LRDICNDVLS LLEKFLIPNA SQAESKVFYL KMKGDYYRYL AEVAAGDDKK GIVDQSQQAY QEAFEISKKE M QPTHPIRL GLALNFSVFY YEILNSPEKA CSLAKTAFDE AIAELDTLSE ESYKDSTLIM QLLRDNLTLW TSDTQGDEAE AG EGGEN

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Macromolecule #2: Serine/threonine-protein kinase B-raf

MacromoleculeName: Serine/threonine-protein kinase B-raf / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 84.697695 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAALSGGGGG GAEPGQALFN GDMEPEAGAG AGAAASSAAD PAIPEEVWNI KQMIKLTQEH IEALLDKFGG EHNPPSIYLE AYEEYTSKL DALQQREQQL LESLGNGTDF SVSSSASMDT VTSSSSSSLS VLPSSLSVFQ NPTDVARSNP KSPQKPIVRV F LPNKQRTV ...String:
MAALSGGGGG GAEPGQALFN GDMEPEAGAG AGAAASSAAD PAIPEEVWNI KQMIKLTQEH IEALLDKFGG EHNPPSIYLE AYEEYTSKL DALQQREQQL LESLGNGTDF SVSSSASMDT VTSSSSSSLS VLPSSLSVFQ NPTDVARSNP KSPQKPIVRV F LPNKQRTV VPARCGVTVR DSLKKALMMR GLIPECCAVY RIQDGEKKPI GWDTDISWLT GEELHVEVLE NVPLTTHNFV RK TFFTLAF CDFCRKLLFQ GFRCQTCGYK FHQRCSTEVP LMCVNYDQLD LLFVSKFFEH HPIPQEEASL AETALTSGSS PSA PASDSI GPQILTSPSP SKSIPIPQPF RPADEDHRNQ FGQRDRSS(SEP)A PNVHINTIEP VNIDDLIRDQ GFRGDGGSTT GLSATPPAS LPGSLTNVKA LQKSPGPQRE RKSSSSSEDR NRMKTLGRRD SSDDWEIPDG QITVGQRIGS GSFGTVYKGK W HGDVAVKM LNVTAPTPQQ LQAFKNEVGV LRKTRHVNIL LFMGYSTKPQ LAIVTQWCEG SSLYHHLHII ETKFEMIKLI DI ARQTAQG MDYLHAKSII HRDLKSNNIF LHEDLTVKIG DFGLATVKSR WSGSHQFEQL SGSILWMAPE VIRMQDKNPY SFQ SDVYAF GIVLYELMTG QLPYSNINNR DQIIFMVGRG YLSPDLSKVR SNCPKAMKRL MAECLKKKRD ERPLFPQILA SIEL LARSL PKIHRSA(SEP)EP SLNRAGFQTE DFSLYACASP KTPIQAGGYG AFPVH

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Macromolecule #3: (1Z)-5-(2-{4-[2-(DIMETHYLAMINO)ETHOXY]PHENYL}-5-PYRIDIN-4-YL-1H-I...

MacromoleculeName: (1Z)-5-(2-{4-[2-(DIMETHYLAMINO)ETHOXY]PHENYL}-5-PYRIDIN-4-YL-1H-IMIDAZOL-4-YL)INDAN-1-ONE OXIME
type: ligand / ID: 3 / Number of copies: 2 / Formula: 215
Molecular weightTheoretical: 453.536 Da
Chemical component information

ChemComp-215:
(1Z)-5-(2-{4-[2-(DIMETHYLAMINO)ETHOXY]PHENYL}-5-PYRIDIN-4-YL-1H-IMIDAZOL-4-YL)INDAN-1-ONE OXIME

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.2 mg/mL
BufferpH: 8
Component:
ConcentrationName
20.0 mMTris
200.0 mMNaClSodium chloride
10.0 mMDTT
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 57.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.89 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 203343
FSC plot (resolution estimation)

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