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- PDB-7zr5: CryoEM structure of HSP90-CDC37-BRAF(V600E)-PP5(closed) complex -

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Basic information

Entry
Database: PDB / ID: 7zr5
TitleCryoEM structure of HSP90-CDC37-BRAF(V600E)-PP5(closed) complex
Components
  • Heat shock protein HSP 90-beta
  • Hsp90 co-chaperone Cdc37
  • Serine/threonine-protein kinase B-raf
  • Serine/threonine-protein phosphatase 5
KeywordsPROTEIN BINDING / Complex
Function / homology
Function and homology information


regulation of type II interferon-mediated signaling pathway / response to arachidonate / HSP90-CDC37 chaperone complex / negative regulation of proteasomal protein catabolic process / Aryl hydrocarbon receptor signalling / peptidyl-serine dephosphorylation / aryl hydrocarbon receptor complex / peptidyl-threonine dephosphorylation / CD4-positive, alpha-beta T cell differentiation / dynein axonemal particle ...regulation of type II interferon-mediated signaling pathway / response to arachidonate / HSP90-CDC37 chaperone complex / negative regulation of proteasomal protein catabolic process / Aryl hydrocarbon receptor signalling / peptidyl-serine dephosphorylation / aryl hydrocarbon receptor complex / peptidyl-threonine dephosphorylation / CD4-positive, alpha-beta T cell differentiation / dynein axonemal particle / histone methyltransferase binding / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / Signalling to p38 via RIT and RIN / receptor ligand inhibitor activity / myeloid progenitor cell differentiation / head morphogenesis / ARMS-mediated activation / positive regulation of type 2 mitophagy / endothelial cell apoptotic process / ATP-dependent protein binding / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / positive regulation of protein localization to cell surface / negative regulation of fibroblast migration / positive regulation of D-glucose transmembrane transport / establishment of protein localization to membrane / positive regulation of axonogenesis / protein kinase regulator activity / protein folding chaperone complex / regulation of T cell differentiation / mitogen-activated protein kinase kinase binding / response to morphine / Negative feedback regulation of MAPK pathway / post-transcriptional regulation of gene expression / Frs2-mediated activation / protein serine/threonine phosphatase activity / regulation of cyclin-dependent protein serine/threonine kinase activity / histone H2AXS140 phosphatase activity / RNA polymerase II CTD heptapeptide repeat Y1 phosphatase activity / RNA polymerase II CTD heptapeptide repeat T4 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity / MAP kinase serine/threonine phosphatase activity / calmodulin-dependent protein phosphatase activity / myosin phosphatase activity / protein-serine/threonine phosphatase / positive regulation of axon regeneration / stress fiber assembly / Respiratory syncytial virus genome replication / positive regulation of transforming growth factor beta receptor signaling pathway / telomerase holoenzyme complex assembly / 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 / face development / MAP kinase kinase activity / regulation of type I interferon-mediated signaling pathway / TPR domain binding / phosphatase activity / synaptic vesicle exocytosis / somatic stem cell population maintenance / Assembly and release of respiratory syncytial virus (RSV) virions / dendritic growth cone / thyroid gland development / The NLRP3 inflammasome / protein phosphatase activator activity / phosphoprotein phosphatase activity / MAP kinase kinase kinase activity / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / HSF1-dependent transactivation / response to unfolded protein / HSF1 activation / postsynaptic modulation of chemical synaptic transmission / telomere maintenance via telomerase / protein targeting / negative regulation of endothelial cell apoptotic process / chaperone-mediated protein complex assembly / Attenuation phase / Purinergic signaling in leishmaniasis infection / RHOBTB2 GTPase cycle / axonal growth cone / response to cAMP / protein dephosphorylation / DNA polymerase binding / positive regulation of stress fiber assembly / supramolecular fiber organization / : / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / heat shock protein binding
Similarity search - Function
Cdc37, Hsp90 binding domain / PP5, C-terminal metallophosphatase domain / PPP domain / PPP5 TPR repeat region / Cdc37, C-terminal / Cdc37, Hsp90 binding / Cdc37, Hsp90-binding domain superfamily / : / Cdc37 C terminal domain / Cdc37 Hsp90 binding domain ...Cdc37, Hsp90 binding domain / PP5, C-terminal metallophosphatase domain / PPP domain / PPP5 TPR repeat region / 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 / Serine/threonine specific protein phosphatases signature. / Protein phosphatase 2A homologues, catalytic domain. / Serine/threonine-specific protein phosphatase/bis(5-nucleosyl)-tetraphosphatase / Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / Metallo-dependent phosphatases / Purple Acid Phosphatase; chain A, domain 2 / : / Tetratricopeptide repeat / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / 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 / Metallo-dependent phosphatase-like / 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 / TPR repeat region circular profile. / TPR repeat profile. / Tetratricopeptide repeats / Tetratricopeptide repeat / Methane Monooxygenase Hydroxylase; Chain G, domain 1 / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / 4-Layer Sandwich / Tetratricopeptide-like helical domain 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 / Up-down Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / Heat shock protein HSP 90-beta / Serine/threonine-protein kinase B-raf / Serine/threonine-protein phosphatase 5 / Hsp90 co-chaperone Cdc37
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsOberoi, J. / Pearl, L.H.
Funding support United Kingdom, 1items
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, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 14, 2022Provider: repository / Type: Initial release
Revision 1.1Dec 21, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 6, 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

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Heat shock protein HSP 90-beta
B: Heat shock protein HSP 90-beta
C: Hsp90 co-chaperone Cdc37
K: Serine/threonine-protein kinase B-raf
P: Serine/threonine-protein phosphatase 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)367,2707
Polymers366,2565
Non-polymers1,0142
Water00
1


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

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Components

#1: Protein Heat shock protein HSP 90-beta / HSP 90 / Heat shock 84 kDa / HSP 84 / HSP84


Mass: 86223.469 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AB1, HSP90B, HSPC2, HSPCB / Production host: Spodoptera (butterflies/moths) / References: UniProt: P08238
#2: Protein Hsp90 co-chaperone Cdc37 / Hsp90 chaperone protein kinase-targeting subunit / p50Cdc37


Mass: 46853.816 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDC37, CDC37A / Production host: Spodoptera (butterflies/moths) / References: UniProt: Q16543
#3: Protein Serine/threonine-protein kinase B-raf / Proto-oncogene B-Raf / p94 / v-Raf murine sarcoma viral oncogene homolog B1


Mass: 90934.508 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Spodoptera (butterflies/moths)
References: UniProt: P15056, non-specific serine/threonine protein kinase
#4: Protein Serine/threonine-protein phosphatase 5 / PP5 / Protein phosphatase T / PP-T / PPT


Mass: 56020.387 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP5C, PPP5 / Production host: Escherichia coli (E. coli)
References: UniProt: P53041, protein-serine/threonine phosphatase
#5: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
Has ligand of interestY
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

Component
IDNameTypeEntity IDParent-IDSource
1HSP90-CDC37-BRAF(V600E)-PP5 (closed) complexCOMPLEX#1-#40RECOMBINANT
2Heat shock protein HSP 90-beta, Hsp90 co-chaperone Cdc37 and Serine/threonine-protein kinase B-rafCOMPLEX#1-#31RECOMBINANT
3Serine/threonine-protein phosphatase 5COMPLEX#41RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Spodoptera (butterflies/moths)7106
33Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 / Nominal defocus max: 2500 nm / Nominal defocus min: 1300 nm
Image recordingElectron dose: 45 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameCategory
4cryoSPARCCTF correction
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 105063 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00917878
ELECTRON MICROSCOPYf_angle_d0.99324046
ELECTRON MICROSCOPYf_dihedral_angle_d5.0162347
ELECTRON MICROSCOPYf_chiral_restr0.0432616
ELECTRON MICROSCOPYf_plane_restr0.0063084

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