+Open data
-Basic information
Entry | Database: PDB / ID: 7zr5 | ||||||
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Title | CryoEM structure of HSP90-CDC37-BRAF(V600E)-PP5(closed) complex | ||||||
Components |
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Keywords | PROTEIN BINDING / Complex | ||||||
Function / homology | Function and homology information regulation of type II interferon-mediated signaling pathway / : / response to arachidonic acid / HSP90-CDC37 chaperone complex / positive regulation of cyclin-dependent protein kinase activity / positive regulation of mitophagy in response to mitochondrial depolarization / negative regulation of proteasomal protein catabolic process / Aryl hydrocarbon receptor signalling / peptidyl-serine dephosphorylation / peptidyl-threonine dephosphorylation ...regulation of type II interferon-mediated signaling pathway / : / response to arachidonic acid / HSP90-CDC37 chaperone complex / positive regulation of cyclin-dependent protein kinase activity / positive regulation of mitophagy in response to mitochondrial depolarization / negative regulation of proteasomal protein catabolic process / Aryl hydrocarbon receptor signalling / peptidyl-serine dephosphorylation / peptidyl-threonine dephosphorylation / aryl hydrocarbon receptor complex / dynein axonemal particle / trehalose metabolism in response to stress / CD4-positive, alpha-beta T cell differentiation / histone methyltransferase binding / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / head morphogenesis / protein kinase regulator activity / Signalling to p38 via RIT and RIN / myeloid progenitor cell differentiation / positive regulation of protein localization to cell surface / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / endothelial cell apoptotic process / response to morphine / negative regulation of fibroblast migration / ATP-dependent protein binding / positive regulation of glucose transmembrane transport / establishment of protein localization to membrane / protein folding chaperone complex / mitogen-activated protein kinase kinase binding / negative regulation of protein metabolic process / regulation of T cell differentiation / Negative feedback regulation of MAPK pathway / positive regulation of tau-protein kinase activity / myosin phosphatase activity / post-transcriptional regulation of gene expression / protein serine/threonine phosphatase activity / telomerase holoenzyme complex assembly / positive regulation of axonogenesis / Frs2-mediated activation / 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 / protein-serine/threonine phosphatase / stress fiber assembly / TPR domain binding / positive regulation of axon regeneration / face development / synaptic vesicle exocytosis / positive regulation of transforming growth factor beta receptor signaling pathway / regulation of cyclin-dependent protein serine/threonine kinase activity / phosphatase activity / dendritic growth cone / somatic stem cell population maintenance / phosphoprotein phosphatase activity / MAP kinase kinase activity / thyroid gland development / regulation of type I interferon-mediated signaling pathway / positive regulation of phosphoprotein phosphatase activity / Sema3A PAK dependent Axon repulsion / The NLRP3 inflammasome / regulation of protein ubiquitination / HSF1-dependent transactivation / telomere maintenance via telomerase / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / response to unfolded protein / MAP kinase kinase kinase activity / HSF1 activation / protein targeting / chaperone-mediated protein complex assembly / Attenuation phase / RHOBTB2 GTPase cycle / Purinergic signaling in leishmaniasis infection / supramolecular fiber organization / DNA polymerase binding / negative regulation of endothelial cell apoptotic process / axonal growth cone / positive regulation of substrate adhesion-dependent cell spreading / Signaling by ERBB2 / response to cAMP / positive regulation of stress fiber assembly / positive regulation of telomerase activity / ERK1 and ERK2 cascade / heat shock protein binding / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / cellular response to calcium ion / cellular response to interleukin-4 / nitric-oxide synthase regulator activity / substrate adhesion-dependent cell spreading Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å | ||||||
Authors | Oberoi, J. / Pearl, L.H. | ||||||
Funding support | United Kingdom, 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7zr5.cif.gz | 411.3 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7zr5.ent.gz | 322.1 KB | Display | PDB format |
PDBx/mmJSON format | 7zr5.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/zr/7zr5 ftp://data.pdbj.org/pub/pdb/validation_reports/zr/7zr5 | HTTPS FTP |
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-Related structure data
Related structure data | 14883MC 7zr0C 7zr6C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | 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 | | 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 | | 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 | | 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 | Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
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Source (natural) |
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Source (recombinant) |
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Buffer solution | pH: 7.5 | ||||||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2500 nm / Nominal defocus min: 1300 nm |
Image recording | Electron dose: 45 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.20.1_4487: / Classification: refinement | ||||||||||||||||||||||||
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EM software |
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CTF correction | Type: NONE | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 105063 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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