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- EMDB-43676: Cryo-EM Structure of the BRAF V600E monomer bound to GDC0879 -

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Basic information

Entry
Database: EMDB / ID: EMD-43676
TitleCryo-EM Structure of the BRAF V600E monomer bound to GDC0879
Map dataFull map of the BRAF V600E - 14-3-3 complex bound to GDC-0879
Sample
  • Complex: BRAF V600E - 14-3-3 complex bound to GDC-0879
    • Protein or peptide: Serine/threonine-protein kinase B-raf
    • Protein or peptide: 14-3-3 protein zeta/delta
KeywordsBRAF Kinase Oncogenic Mutant Monomer / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


synaptic target recognition / Golgi reassembly / NOTCH4 Activation and Transmission of Signal to the Nucleus / respiratory system process / establishment of Golgi localization / tube formation / Signalling to p38 via RIT and RIN / ARMS-mediated activation / regulation of synapse maturation / SHOC2 M1731 mutant abolishes MRAS complex function ...synaptic target recognition / Golgi reassembly / NOTCH4 Activation and Transmission of Signal to the Nucleus / respiratory system process / establishment of Golgi localization / tube formation / Signalling to p38 via RIT and RIN / ARMS-mediated activation / regulation of synapse maturation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling / positive regulation of D-glucose transmembrane transport / establishment of protein localization to membrane / negative regulation of protein localization to nucleus / KSRP (KHSRP) binds and destabilizes mRNA / Negative feedback regulation of MAPK pathway / GP1b-IX-V activation signalling / Frs2-mediated activation / MAP kinase kinase activity / lung development / Regulation of localization of FOXO transcription factors / Interleukin-3, Interleukin-5 and GM-CSF signaling / positive regulation of peptidyl-serine phosphorylation / phosphoserine residue binding / Activation of BAD and translocation to mitochondria / regulation of ERK1 and ERK2 cascade / MAP kinase kinase kinase activity / postsynaptic modulation of chemical synaptic transmission / cellular response to glucose starvation / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / negative regulation of TORC1 signaling / animal organ morphogenesis / Transcriptional and post-translational regulation of MITF-M expression and activity / cellular response to calcium ion / negative regulation of innate immune response / hippocampal mossy fiber to CA3 synapse / TP53 Regulates Metabolic Genes / Translocation of SLC2A4 (GLUT4) to the plasma membrane / regulation of protein stability / RAF activation / protein sequestering activity / Signaling by high-kinase activity BRAF mutants / Spry regulation of FGF signaling / Deactivation of the beta-catenin transactivating complex / MAP2K and MAPK activation / Negative regulation of NOTCH4 signaling / epidermal growth factor receptor signaling pathway / intracellular protein localization / 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 / MAPK cascade / Negative regulation of MAPK pathway / Signaling by BRAF and RAF1 fusions / melanosome / angiogenesis / cell body / scaffold protein binding / protein phosphatase binding / blood microparticle / DNA-binding transcription factor binding / vesicle / transmembrane transporter binding / positive regulation of ERK1 and ERK2 cascade / protein kinase activity / protein phosphorylation / non-specific serine/threonine protein kinase / postsynapse / neuron projection / cadherin binding / protein domain specific binding / protein serine kinase activity / focal adhesion / ubiquitin protein ligase binding / protein serine/threonine kinase activity / positive regulation of gene expression / calcium ion binding / negative regulation of apoptotic process / protein kinase binding / negative regulation of transcription by RNA polymerase II / glutamatergic synapse / signal transduction / mitochondrion / : / RNA binding / extracellular exosome / nucleoplasm / zinc ion binding / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
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) ...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: 4.32 Å
AuthorsLavoie H / Lajoie D / Jin T / Decossas M / Maisonneuve P / Therrien M
Funding support Canada, 1 items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)FDN-388023 Canada
CitationJournal: Science / Year: 2025
Title: BRAF oncogenic mutants evade autoinhibition through a common mechanism.
Authors: Hugo Lavoie / Ting Jin / Driss Lajoie / Marion Decossas / Patrick Gendron / Bing Wang / Frantisek Filandr / Malha Sahmi / Chang Hwa Jo / Sandra Weber / Geneviève Arseneault / Sasmita ...Authors: Hugo Lavoie / Ting Jin / Driss Lajoie / Marion Decossas / Patrick Gendron / Bing Wang / Frantisek Filandr / Malha Sahmi / Chang Hwa Jo / Sandra Weber / Geneviève Arseneault / Sasmita Tripathy / Pierre Beaulieu / Doris A Schuetz / David C Schriemer / Anne Marinier / William J Rice / Pierre Maisonneuve / Marc Therrien /
Abstract: Uncontrolled activation of the rat sarcoma (RAS)-extracellular signal-regulated kinase (ERK) pathway drives tumor growth, often because of oncogenic BRAF mutations. BRAF regulation, involving ...Uncontrolled activation of the rat sarcoma (RAS)-extracellular signal-regulated kinase (ERK) pathway drives tumor growth, often because of oncogenic BRAF mutations. BRAF regulation, involving monomeric autoinhibition and activation by dimerization, has been intensely scrutinized, but mechanisms enabling oncogenic mutants to evade regulation remain unclear. By using cryo-electron microscopy, we solved the three-dimensional structures of the three oncogenic BRAF mutant classes, including the common V600E variant. These mutations disrupted wild-type BRAF's autoinhibited state, mediated by interactions between the cysteine-rich domain and kinase domain, thereby shifting the kinase domain into a preactivated conformation. This structural change likely results from helix αC displacement. PLX8394, a BRAF inhibitor that stabilizes helix αC in an inactive conformation, restored the autoinhibited conformation of oncogenic BRAF, explaining the properties of this class of compounds.
History
DepositionFeb 9, 2024-
Header (metadata) releaseMay 28, 2025-
Map releaseMay 28, 2025-
UpdateJun 25, 2025-
Current statusJun 25, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43676.png

Downloads & links

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Map

FileDownload / File: emd_43676.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFull map of the BRAF V600E - 14-3-3 complex bound to GDC-0879
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 211.2 Å		0.83 Å/pix.
x 256 pix.
= 211.2 Å		0.83 Å/pix.
x 256 pix.
= 211.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.10039163 - 0.24818507
Average (Standard dev.)0.00036629435 (±0.007556206)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 211.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map A of the BRAF V600E - 14-3-3 complex bound to GDC-0879

Fileemd_43676_half_map_1.map
AnnotationHalf map A of the BRAF V600E - 14-3-3 complex bound to GDC-0879
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B of the BRAF V600E - 14-3-3 complex bound to GDC-0879

Fileemd_43676_half_map_2.map
AnnotationHalf map B of the BRAF V600E - 14-3-3 complex bound to GDC-0879
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : BRAF V600E - 14-3-3 complex bound to GDC-0879

EntireName: BRAF V600E - 14-3-3 complex bound to GDC-0879
Components
  • Complex: BRAF V600E - 14-3-3 complex bound to GDC-0879
    • Protein or peptide: Serine/threonine-protein kinase B-raf
    • Protein or peptide: 14-3-3 protein zeta/delta

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Supramolecule #1: BRAF V600E - 14-3-3 complex bound to GDC-0879

SupramoleculeName: BRAF V600E - 14-3-3 complex bound to GDC-0879 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 141 KDa

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Macromolecule #1: Serine/threonine-protein kinase B-raf

MacromoleculeName: Serine/threonine-protein kinase B-raf / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 84.784727 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GMAALSGGGG GGAEPGQALF NGDMEPEAGA GAGAAASSAA DPAIPEEVWN IKQMIKLTQE HIEALLDKFG GEHNPPSIYL EAYEEYTSK LDALQQREQQ LLESLGNGTD FSVSSSASMD TVTSSSSSSL SVLPSSLSVF QNPTDVARSN PKSPQKPIVR V FLPNKQRT ...String:
GMAALSGGGG GGAEPGQALF NGDMEPEAGA GAGAAASSAA DPAIPEEVWN IKQMIKLTQE HIEALLDKFG GEHNPPSIYL EAYEEYTSK LDALQQREQQ LLESLGNGTD FSVSSSASMD TVTSSSSSSL SVLPSSLSVF QNPTDVARSN PKSPQKPIVR V FLPNKQRT VVPARCGVTV RDSLKKALMM RGLIPECCAV YRIQDGEKKP IGWDTDISWL TGEELHVEVL ENVPLTTHNF VR KTFFTLA FCDFCRKLLF QGFRCQTCGY KFHQRCSTEV PLMCVNYDQL DLLFVSKFFE HHPIPQEEAS LAETALTSGS SPS APASDS IGPQILTSPS PSKSIPIPQP FRPADEDHRN QFGQRDRSS(SEP) APNVHINTIE PVNIDDLIRD QGFRGDGGST TGLSATPPA SLPGSLTNVK ALQKSPGPQR ERKSSSSSED RNRMKTLGRR DSSDDWEIPD GQITVGQRIG SGSFGTVYKG K WHGDVAVK MLNVTAPTPQ QLQAFKNEVG VLRKTRHVNI LLFMGYSTKP QLAIVTQWCE GSSLYHHLHI IETKFEMIKL ID IARQTAQ GMDYLHAKSI IHRDLKSNNI FLHEDLTVKI GDFGLATEKS RWSGSHQFEQ LSGSILWMAP EVIRMQDKNP YSF QSDVYA FGIVLYELMT GQLPYSNINN RDQIIFMVGR GYLSPDLSKV RSNCPKAMKR LMAECLKKKR DERPLFPQIL ASIE LLARS LPKIHRSA(SEP)E PSLNRAGFQT EDFSLYACAS PKTPIQAGGY GAFPVH

UniProtKB: Serine/threonine-protein kinase B-raf

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Macromolecule #2: 14-3-3 protein zeta/delta

MacromoleculeName: 14-3-3 protein zeta/delta / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 27.777092 KDa
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

UniProtKB: 14-3-3 protein zeta/delta

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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

Concentration1 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
20.0 mMC8H17N2NaO4SHEPES
137.0 mMNaClSodium Chloride
5.0 mMMgCl2Magnesium Chloride
1.0 mMC9H15O6PTCEP
0.005 mMC19H18N4OGDC-0879
VitrificationCryogen name: ETHANE / Details: Chameleon system (SPT Labtech).

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 51.55 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 4.6000000000000005 µm / Nominal defocus min: 1.7 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: CTFFIND (ver. 4) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.32 Å / Resolution method: FSC 0.143 CUT-OFF
Details: Resolution corresponds to the FSC 0.143 cut-off of the masked map
Number images used: 32966
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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