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- EMDB-14875: CryoEM structure of HSP90-CDC37-BRAF(V600E) complex. -

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Entry
Database: EMDB / ID: EMD-14875
TitleCryoEM structure of HSP90-CDC37-BRAF(V600E) complex.
Map data
Sample
  • Complex: HSP90-CDC37-BRAF(V600E) complex
    • Protein or peptide: Heat shock protein HSP 90-beta
    • Protein or peptide: Hsp90 co-chaperone Cdc37
  • Protein or peptide: Serine/threonine-protein kinase B-raf
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
KeywordsComplex / PROTEIN BINDING / CHAPERONE
Function / homology
Function and homology information


regulation of type II interferon-mediated signaling pathway / HSP90-CDC37 chaperone complex / negative regulation of proteasomal protein catabolic process / Aryl hydrocarbon receptor signalling / aryl hydrocarbon receptor complex / positive regulation of axon regeneration / histone methyltransferase binding / CD4-positive, alpha-beta T cell differentiation / dynein axonemal particle / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment ...regulation of type II interferon-mediated signaling pathway / HSP90-CDC37 chaperone complex / negative regulation of proteasomal protein catabolic process / Aryl hydrocarbon receptor signalling / aryl hydrocarbon receptor complex / positive regulation of axon regeneration / histone methyltransferase binding / CD4-positive, alpha-beta T cell differentiation / dynein axonemal particle / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / receptor ligand inhibitor activity / Signalling to p38 via RIT and RIN / head morphogenesis / positive regulation of type 2 mitophagy / ARMS-mediated activation / endothelial cell apoptotic process / myeloid progenitor cell differentiation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / positive regulation of D-glucose transmembrane transport / negative regulation of fibroblast migration / regulation of cyclin-dependent protein serine/threonine kinase activity / ATP-dependent protein binding / positive regulation of protein localization to cell surface / establishment of protein localization to membrane / positive regulation of axonogenesis / protein kinase regulator activity / protein folding chaperone complex / regulation of T cell differentiation / Negative feedback regulation of MAPK pathway / post-transcriptional regulation of gene expression / Frs2-mediated activation / stress fiber assembly / Respiratory syncytial virus genome replication / telomerase holoenzyme complex assembly / positive regulation of transforming growth factor beta receptor signaling pathway / Uptake and function of diphtheria toxin / Drug-mediated inhibition of ERBB2 signaling / Resistance of ERBB2 KD mutants to trastuzumab / Resistance of ERBB2 KD mutants to sapitinib / Resistance of ERBB2 KD mutants to tesevatinib / Resistance of ERBB2 KD mutants to neratinib / Resistance of ERBB2 KD mutants to osimertinib / Resistance of ERBB2 KD mutants to afatinib / Resistance of ERBB2 KD mutants to AEE788 / Resistance of ERBB2 KD mutants to lapatinib / Drug resistance in ERBB2 TMD/JMD mutants / regulation of type I interferon-mediated signaling pathway / dendritic growth cone / TPR domain binding / face development / MAP kinase kinase activity / Assembly and release of respiratory syncytial virus (RSV) virions / thyroid gland development / The NLRP3 inflammasome / protein phosphatase activator activity / synaptic vesicle exocytosis / Sema3A PAK dependent Axon repulsion / somatic stem cell population maintenance / regulation of protein ubiquitination / positive regulation of peptidyl-serine phosphorylation / HSF1-dependent transactivation / MAP kinase kinase kinase activity / response to unfolded protein / HSF1 activation / telomere maintenance via telomerase / Attenuation phase / postsynaptic modulation of chemical synaptic transmission / negative regulation of endothelial cell apoptotic process / chaperone-mediated protein complex assembly / axonal growth cone / protein targeting / RHOBTB2 GTPase cycle / Purinergic signaling in leishmaniasis infection / positive regulation of stress fiber assembly / : / supramolecular fiber organization / DNA polymerase binding / heat shock protein binding / ERK1 and ERK2 cascade / Signaling by ERBB2 / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / positive regulation of substrate adhesion-dependent cell spreading / protein folding chaperone / peptide binding / cellular response to interleukin-4 / substrate adhesion-dependent cell spreading / cellular response to calcium ion / ESR-mediated signaling / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / Constitutive Signaling by Overexpressed ERBB2 / thymus development / placenta development / animal organ morphogenesis / nitric-oxide synthase regulator activity / positive regulation of cell differentiation / Hsp90 protein binding / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants
Similarity search - Function
Cdc37, C-terminal / Cdc37, Hsp90 binding / Cdc37, Hsp90-binding domain superfamily / Cdc37 C terminal domain / Cdc37 Hsp90 binding domain / Cdc37 C terminal domain / Cdc37 Hsp90 binding domain / Cdc37 N terminal kinase binding / Cdc37 / Cdc37, N-terminal domain ...Cdc37, C-terminal / Cdc37, Hsp90 binding / Cdc37, Hsp90-binding domain superfamily / Cdc37 C terminal domain / Cdc37 Hsp90 binding domain / Cdc37 C terminal domain / Cdc37 Hsp90 binding domain / Cdc37 N terminal kinase binding / Cdc37 / Cdc37, N-terminal domain / Cdc37 N terminal kinase binding / 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 / Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Ubiquitin-like domain superfamily / Ribosomal protein S5 domain 2-type fold / 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
Heat shock protein HSP 90-beta / Serine/threonine-protein kinase B-raf / Hsp90 co-chaperone Cdc37
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsOberoi J / Pearl LH
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Wellcome Trust United Kingdom
CitationJournal: Nat Commun / Year: 2022
Title: HSP90-CDC37-PP5 forms a structural platform for kinase dephosphorylation.
Authors: Jasmeen Oberoi / Xavi Aran Guiu / Emily A Outwin / Pascale Schellenberger / Theodoros I Roumeliotis / Jyoti S Choudhary / Laurence H Pearl /
Abstract: Activation of client protein kinases by the HSP90 molecular chaperone system is affected by phosphorylation at multiple sites on HSP90, the kinase-specific co-chaperone CDC37, and the kinase client ...Activation of client protein kinases by the HSP90 molecular chaperone system is affected by phosphorylation at multiple sites on HSP90, the kinase-specific co-chaperone CDC37, and the kinase client itself. Removal of regulatory phosphorylation from client kinases and their release from the HSP90-CDC37 system depends on the Ser/Thr phosphatase PP5, which associates with HSP90 via its N-terminal TPR domain. Here, we present the cryoEM structure of the oncogenic protein kinase client BRAF bound to HSP90-CDC37, showing how the V600E mutation favours BRAF association with HSP90-CDC37. Structures of HSP90-CDC37-BRAF complexes with PP5 in autoinhibited and activated conformations, together with proteomic analysis of its phosphatase activity on BRAF and CRAF, reveal how PP5 is activated by recruitment to HSP90 complexes. PP5 comprehensively dephosphorylates client proteins, removing interaction sites for regulatory partners such as 14-3-3 proteins and thus performing a 'factory reset' of the kinase prior to release.
History
DepositionMay 3, 2022-
Header (metadata) releaseDec 14, 2022-
Map releaseDec 14, 2022-
UpdateJul 9, 2025-
Current statusJul 9, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_14875.png

Downloads & links

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Map

FileDownload / File: emd_14875.map.gz / Format: CCP4 / Size: 134.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 328 pix.
= 282.08 Å		0.86 Å/pix.
x 328 pix.
= 282.08 Å		0.86 Å/pix.
x 328 pix.
= 282.08 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.02
Minimum - Maximum-0.001692775 - 1.8435149
Average (Standard dev.)0.0012535704 (±0.02553145)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions328328328
Spacing328328328
CellA=B=C: 282.08002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_14875_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_14875_half_map_2.map
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Sample components

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Entire : HSP90-CDC37-BRAF(V600E) complex

EntireName: HSP90-CDC37-BRAF(V600E) complex
Components
  • Complex: HSP90-CDC37-BRAF(V600E) complex
    • Protein or peptide: Heat shock protein HSP 90-beta
    • Protein or peptide: Hsp90 co-chaperone Cdc37
  • Protein or peptide: Serine/threonine-protein kinase B-raf
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE

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Supramolecule #1: HSP90-CDC37-BRAF(V600E) complex

SupramoleculeName: HSP90-CDC37-BRAF(V600E) complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Heat shock protein HSP 90-beta

MacromoleculeName: Heat shock protein HSP 90-beta / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 86.223469 KDa
Recombinant expressionOrganism: Spodoptera (butterflies/moths)
SequenceString: MRGSHHHHHH HHGMALEVLF QGPSAMPEEV HHGEEEVETF AFQAEIAQLM SLIINTFYSN KEIFLRELIS NASDALDKIR YESLTDPSK LDSGKELKID IIPNPQERTL TLVDTGIGMT KADLINNLGT IAKSGTKAFM EALQAGADIS MIGQFGVGFY S AYLVAEKV ...String:
MRGSHHHHHH HHGMALEVLF QGPSAMPEEV HHGEEEVETF AFQAEIAQLM SLIINTFYSN KEIFLRELIS NASDALDKIR YESLTDPSK LDSGKELKID IIPNPQERTL TLVDTGIGMT KADLINNLGT IAKSGTKAFM EALQAGADIS MIGQFGVGFY S AYLVAEKV VVITKHNDDE QYAWESSAGG SFTVRADHGE PIGRGTKVIL HLKEDQTEYL EERRVKEVVK KHSQFIGYPI TL YLEKERE KEISDDEAEE EKGEKEEEDK DDEEKPKIED VGSDEEDDSG KDKKKKTKKI KEKYIDQEEL NKTKPIWTRN PDD ITQEEY GEFYKSLTND WEDHLAVKHF SVEGQLEFRA LLFIPRRAPF DLFENKKKKN NIKLYVRRVF IMDSCDELIP EYLN FIRGV VDSEDLPLNI SREMLQQSKI LKVIRKNIVK KCLELFSELA EDKENYKKFY EAFSKNLKLG IHEDSTNRRR LSELL RYHT SQSGDEMTSL SEYVSRMKET QKSIYYITGE SKEQVANSAF VERVRKRGFE VVYMTEPIDE YCVQQLKEFD GKSLVS VTK EGLELPEDEE EKKKMEESKA KFENLCKLMK EILDKKVEKV TISNRLVSSP CCIVTSTYGW TANMERIMKA QALRDNS TM GYMMAKKHLE INPDHPIVET LRQKAEADKN DKAVKDLVVL LFETALLSSG FSLEDPQTHS NRIYRMIKLG LGIDEDEV A AEEPNAAVPD EIPPLEGDED ASRMEEVD

UniProtKB: Heat shock protein HSP 90-beta

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Macromolecule #2: Hsp90 co-chaperone Cdc37

MacromoleculeName: Hsp90 co-chaperone Cdc37 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.853816 KDa
Recombinant expressionOrganism: Spodoptera (butterflies/moths)
SequenceString: MVDYSVWDHI EV(SEP)DDEDETH PNIDTASLFR WRHQARVERM EQFQKEKEEL DRGCRECKRK VAECQRKLKE LEVAEG GKA ELERLQAEAQ QLRKEERSWE QKLEEMRKKE KSMPWNVDTL SKDGFSKSMV NTKPEKTEED SEEVREQKHK TFVEKYE KQ IKHFGMLRRW ...String:
MVDYSVWDHI EV(SEP)DDEDETH PNIDTASLFR WRHQARVERM EQFQKEKEEL DRGCRECKRK VAECQRKLKE LEVAEG GKA ELERLQAEAQ QLRKEERSWE QKLEEMRKKE KSMPWNVDTL SKDGFSKSMV NTKPEKTEED SEEVREQKHK TFVEKYE KQ IKHFGMLRRW DDSQKYLSDN VHLVCEETAN YLVIWCIDLE VEEKCALMEQ VAHQTIVMQF ILELAKSLKV DPRACFRQ F FTKIKTADRQ YMEGFNDELE AFKERVRGRA KLRIEKAMKE YEEEERKKRL GPGGLDPVEV YESLPEELQK CFDVKDVQM LQDAISKMDP TDAKYHMQRC IDSGLWVPNS KASEAKEGEE AGPGDPLLEA VPKTGDEKDV SVLEVLFQGP LEHHHHHHHH

UniProtKB: Hsp90 co-chaperone Cdc37

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Macromolecule #3: Serine/threonine-protein kinase B-raf

MacromoleculeName: Serine/threonine-protein kinase B-raf / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 90.934508 KDa
Recombinant expressionOrganism: Spodoptera (butterflies/moths)
SequenceString: MGGSHHHHHH HHGGSWSHPQ FEKGGGSGGG SGGGSWSHPQ FEKGAETAVP NSLEVLFQGP SAMAALSGGG GGGAEPGQAL FNGDMEPEA GAGAGAAASS AADPAIPEEV WNIKQMIKLT QEHIEALLDK FGGEHNPPSI YLEAYEEYTS KLDALQQREQ Q LLESLGNG ...String:
MGGSHHHHHH HHGGSWSHPQ FEKGGGSGGG SGGGSWSHPQ FEKGAETAVP NSLEVLFQGP SAMAALSGGG GGGAEPGQAL FNGDMEPEA GAGAGAAASS AADPAIPEEV WNIKQMIKLT QEHIEALLDK FGGEHNPPSI YLEAYEEYTS KLDALQQREQ Q LLESLGNG TDFSVSSSAS MDTVTSSSSS SLSVLPSSLS VFQNPTDVAR SNPKSPQKPI VRVFLPNKQR TVVPARCGVT VR DSLKKAL MMRGLIPECC AVYRIQDGEK KPIGWDTDIS WLTGEELHVE VLENVPLTTH NFVRKTFFTL AFCDFCRKLL FQG FRCQTC GYKFHQRCST EVPLMCVNYD QLDLLFVSKF FEHHPIPQEE ASLAETALTS GSSPSAPASD SIGPQILTSP SPSK SIPIP QPFRPADEDH RNQFGQRDRS SSAPNVHINT IEPVNIDDLI RDQGFRGDGG STTGLSATPP ASLPGSLTNV KALQK SPGP QRERKSSSSS EDRNRMKTLG RRDSSDDWEI PDGQITVGQR IGSGSFGTVY KGKWHGDVAV KMLNVTAPTP QQLQAF KNE VGVLRKTRHV NILLFMGYST KPQLAIVTQW CEGSSLYHHL HIIETKFEMI KLIDIARQTA QGMDYLHAKS IIHRDLK SN NIFLHEDLTV KIGDFGLATE KSRWSGSHQF EQLSGSILWM APEVIRMQDK NPYSFQSDVY AFGIVLYELM TGQLPYSN I NNRDQIIFMV GRGYLSPDLS KVRSNCPKAM KRLMAECLKK KRDERPLFPQ ILASIELLAR SLPKIHRSAS EPSLNRAGF QTEDFSLYAC ASPKTPIQAG GYGAFPVH

UniProtKB: Serine/threonine-protein kinase B-raf

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Macromolecule #4: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 4 / Number of copies: 2 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.3 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC / Type: NONE
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 400624
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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