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Yorodumi- EMDB-14883: CryoEM structure of HSP90-CDC37-BRAF(V600E)-PP5(closed) complex -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-14883 | |||||||||
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Title | CryoEM structure of HSP90-CDC37-BRAF(V600E)-PP5(closed) complex | |||||||||
Map data | ||||||||||
Sample |
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Function / homology | Function and homology information regulation of type II interferon-mediated signaling pathway / receptor ligand inhibitor activity / response to arachidonate / HSP90-CDC37 chaperone complex / 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 ...regulation of type II interferon-mediated signaling pathway / receptor ligand inhibitor activity / response to arachidonate / HSP90-CDC37 chaperone complex / 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 / 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 / Signalling to p38 via RIT and RIN / head morphogenesis / 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 / positive regulation of protein localization to cell surface / ATP-dependent protein binding / negative regulation of fibroblast migration / positive regulation of glucose transmembrane transport / establishment of protein localization to membrane / response to morphine / protein kinase regulator activity / protein folding chaperone complex / MAP kinase kinase kinase activity / mitogen-activated protein kinase kinase binding / regulation of T cell differentiation / Negative feedback regulation of MAPK pathway / post-transcriptional regulation of gene expression / telomerase holoenzyme complex assembly / myosin phosphatase activity / positive regulation of axonogenesis / Respiratory syncytial virus genome replication / Uptake and function of diphtheria toxin / protein serine/threonine phosphatase activity / Frs2-mediated activation / regulation of cyclin-dependent protein serine/threonine kinase activity / 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 / TPR domain binding / stress fiber assembly / positive regulation of axon regeneration / positive regulation of transforming growth factor beta receptor signaling pathway / Assembly and release of respiratory syncytial virus (RSV) virions / face development / dendritic growth cone / phosphatase activity / synaptic vesicle exocytosis / MAP kinase kinase activity / somatic stem cell population maintenance / regulation of type I interferon-mediated signaling pathway / : / thyroid gland development / phosphoprotein phosphatase activity / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / The NLRP3 inflammasome / Signaling by ERBB2 / telomere maintenance via telomerase / HSF1-dependent transactivation / response to unfolded protein / chaperone-mediated protein complex assembly / HSF1 activation / Attenuation phase / protein targeting / cellular response to interleukin-4 / RHOBTB2 GTPase cycle / negative regulation of endothelial cell apoptotic process / axonal growth cone / Purinergic signaling in leishmaniasis infection / DNA polymerase binding / supramolecular fiber organization / positive regulation of substrate adhesion-dependent cell spreading / chaperone-mediated protein folding / positive regulation of stress fiber assembly / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / protein folding chaperone / response to cAMP / heat shock protein binding / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / cellular response to calcium ion / ERK1 and ERK2 cascade / nitric-oxide synthase regulator activity / protein dephosphorylation / Constitutive Signaling by Overexpressed ERBB2 Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.9 Å | |||||||||
Authors | Oberoi J / Pearl LH | |||||||||
Funding support | United Kingdom, 1 items
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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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_14883.map.gz | 119.8 MB | EMDB map data format | |
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Header (meta data) | emd-14883-v30.xml emd-14883.xml | 19.8 KB 19.8 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_14883_fsc.xml | 11.7 KB | Display | FSC data file |
Images | emd_14883.png | 82.4 KB | ||
Others | emd_14883_half_map_1.map.gz emd_14883_half_map_2.map.gz | 106.2 MB 106.5 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-14883 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-14883 | HTTPS FTP |
-Related structure data
Related structure data | 7zr5MC 7zr0C 7zr6C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_14883.map.gz / Format: CCP4 / Size: 134.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 0.86 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #1
File | emd_14883_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_14883_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : HSP90-CDC37-BRAF(V600E)-PP5 (closed) complex
Entire | Name: HSP90-CDC37-BRAF(V600E)-PP5 (closed) complex |
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Components |
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-Supramolecule #1: HSP90-CDC37-BRAF(V600E)-PP5 (closed) complex
Supramolecule | Name: HSP90-CDC37-BRAF(V600E)-PP5 (closed) complex / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#4 |
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-Supramolecule #2: Heat shock protein HSP 90-beta, Hsp90 co-chaperone Cdc37 and Seri...
Supramolecule | Name: Heat shock protein HSP 90-beta, Hsp90 co-chaperone Cdc37 and Serine/threonine-protein kinase B-raf type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#3 |
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Source (natural) | Organism: Homo sapiens (human) |
-Supramolecule #3: Serine/threonine-protein phosphatase 5
Supramolecule | Name: Serine/threonine-protein phosphatase 5 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #4 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Heat shock protein HSP 90-beta
Macromolecule | Name: Heat shock protein HSP 90-beta / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 86.223469 KDa |
Recombinant expression | Organism: Spodoptera (butterflies/moths) |
Sequence | String: 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 |
-Macromolecule #2: Hsp90 co-chaperone Cdc37
Macromolecule | Name: Hsp90 co-chaperone Cdc37 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 46.853816 KDa |
Recombinant expression | Organism: Spodoptera (butterflies/moths) |
Sequence | String: 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 |
-Macromolecule #3: Serine/threonine-protein kinase B-raf
Macromolecule | Name: 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 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 90.934508 KDa |
Recombinant expression | Organism: Spodoptera (butterflies/moths) |
Sequence | String: 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 |
-Macromolecule #4: Serine/threonine-protein phosphatase 5
Macromolecule | Name: Serine/threonine-protein phosphatase 5 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO / EC number: protein-serine/threonine phosphatase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 56.020387 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: DEPPADGALK RAEELKTQAN DYFKAKDYEN AIKFYSQAIE LNPSNAIYYG NRSLAYLRTE CYGYALGDAT RAIELDKKYI KGYYRRAAS NMALGKFRAA LRDYETVVKV KPHDKDAKMK YQECNKIVKQ KAFERAIAGD EHKRSVVDSL DIESMTIEDE Y SGPKLEDG ...String: DEPPADGALK RAEELKTQAN DYFKAKDYEN AIKFYSQAIE LNPSNAIYYG NRSLAYLRTE CYGYALGDAT RAIELDKKYI KGYYRRAAS NMALGKFRAA LRDYETVVKV KPHDKDAKMK YQECNKIVKQ KAFERAIAGD EHKRSVVDSL DIESMTIEDE Y SGPKLEDG KVTISFMKEL MQWYKDQKKL HRKCAYQILV QVKEVLSKLS TLVETTLKET EKITVCGDTH GQFYDLLNIF EL NGLPSET NPYIFNGDFV DRGSFSVEVI LTLFGFKLLY PDHFHLLRGN HETDNMNQIY GFEGEVKAKY TAQMYELFSE VFE WLPLAQ CINGKVLIMH GGLFSEDGVT LDDIRKIERN RQPPDSGPMC DLLWSDPQPQ NGRSISKRGV SCQFGPDVTK AFLE ENNLD YIIRSHEVKA EGYEVAHGGR CVTVFSAPNY CDQMGNKASY IHLQGSDLRP QFHQFTAVPH PNVKPMAYAN TLLQL GMMH HHHHH |
-Macromolecule #5: ADENOSINE-5'-TRIPHOSPHATE
Macromolecule | Name: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 5 / Number of copies: 2 / Formula: ATP |
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Molecular weight | Theoretical: 507.181 Da |
Chemical component information | ChemComp-ATP: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 45.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination 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 |