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- PDB-5fwk: Atomic cryoEM structure of Hsp90-Cdc37-Cdk4 complex -

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Basic information

Entry
Database: PDB / ID: 5fwk
TitleAtomic cryoEM structure of Hsp90-Cdc37-Cdk4 complex
Components
  • CYCLIN-DEPENDENT KINASE 4
  • HEAT SHOCK PROTEIN HSP 90 BETA
  • HSP90 CO-CHAPERONE CDC37
KeywordsSIGNALING PROTEIN / HSP90 / CDC37 / CDK4 / CHAPERONE / KINASE / UNFOLDING
Function / homology
Function and homology information


cyclin D3-CDK4 complex / cyclin D1-CDK4 complex / cyclin D2-CDK4 complex / Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 / Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 / cellular response to ionomycin / regulation of transcription initiation by RNA polymerase II / Drug-mediated inhibition of CDK4/CDK6 activity / regulation of type II interferon-mediated signaling pathway / Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 ...cyclin D3-CDK4 complex / cyclin D1-CDK4 complex / cyclin D2-CDK4 complex / Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 / Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 / cellular response to ionomycin / regulation of transcription initiation by RNA polymerase II / Drug-mediated inhibition of CDK4/CDK6 activity / regulation of type II interferon-mediated signaling pathway / Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 / Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 / regulation of type B pancreatic cell proliferation / HSP90-CDC37 chaperone complex / negative regulation of proteasomal protein catabolic process / Aryl hydrocarbon receptor signalling / aryl hydrocarbon receptor complex / dynein axonemal particle / histone methyltransferase binding / Transcriptional regulation by RUNX2 / cellular response to phorbol 13-acetate 12-myristate / receptor ligand inhibitor activity / positive regulation of type 2 mitophagy / ATP-dependent protein binding / positive regulation of protein localization to cell surface / protein kinase regulator activity / protein folding chaperone complex / cyclin-dependent protein serine/threonine kinase regulator activity / post-transcriptional regulation of gene expression / regulation of cyclin-dependent protein serine/threonine kinase activity / Respiratory syncytial virus genome replication / positive regulation of transforming growth factor beta receptor signaling pathway / telomerase holoenzyme complex assembly / PTK6 Regulates Cell Cycle / 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 / TPR domain binding / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / Assembly and release of respiratory syncytial virus (RSV) virions / dendritic growth cone / The NLRP3 inflammasome / protein phosphatase activator activity / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / HSF1-dependent transactivation / bicellular tight junction / response to unfolded protein / cyclin-dependent kinase / HSF1 activation / telomere maintenance via telomerase / cyclin-dependent protein serine/threonine kinase activity / protein targeting / chaperone-mediated protein complex assembly / Attenuation phase / Purinergic signaling in leishmaniasis infection / RHOBTB2 GTPase cycle / axonal growth cone / cyclin-dependent protein kinase holoenzyme complex / DNA polymerase binding / supramolecular fiber organization / : / regulation of G2/M transition of mitotic cell cycle / positive regulation of G2/M transition of mitotic cell cycle / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / heat shock protein binding / Signaling by ERBB2 / protein folding chaperone / nitric-oxide synthase regulator activity / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / cyclin binding / cellular response to interleukin-4 / peptide binding / Constitutive Signaling by Overexpressed ERBB2 / ESR-mediated signaling / Ubiquitin-dependent degradation of Cyclin D / positive regulation of cell differentiation / placenta development / Hsp90 protein binding / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / tau protein binding / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Oncogene Induced Senescence / Signaling by ERBB2 KD Mutants / Transcriptional regulation of white adipocyte differentiation / Meiotic recombination / Regulation of actin dynamics for phagocytic cup formation / Regulation of necroptotic cell death / kinase binding
Similarity search - Function
Ribosomal Protein S5; domain 2 - #80 / 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 ...Ribosomal Protein S5; domain 2 - #80 / 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 / Ribosomal Protein S5; domain 2 / 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-like ATPase, C-terminal domain / Heat Shock Protein 90 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / : / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / Ribosomal protein S5 domain 2-type fold / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / Heat shock protein HSP 90-beta / Cyclin-dependent kinase 4 / Hsp90 co-chaperone Cdc37
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsVerba, K.A. / Wang, R.Y.R. / Arakawa, A. / Liu, Y. / Yokoyama, S. / Agard, D.A.
CitationJournal: Science / Year: 2016
Title: Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase.
Authors: Kliment A Verba / Ray Yu-Ruei Wang / Akihiko Arakawa / Yanxin Liu / Mikako Shirouzu / Shigeyuki Yokoyama / David A Agard /
Abstract: The Hsp90 molecular chaperone and its Cdc37 cochaperone help stabilize and activate more than half of the human kinome. However, both the mechanism by which these chaperones assist their "client" ...The Hsp90 molecular chaperone and its Cdc37 cochaperone help stabilize and activate more than half of the human kinome. However, both the mechanism by which these chaperones assist their "client" kinases and the reason why some kinases are addicted to Hsp90 while closely related family members are independent are unknown. Our structural understanding of these interactions is lacking, as no full-length structures of human Hsp90, Cdc37, or either of these proteins with a kinase have been elucidated. Here we report a 3.9 angstrom cryo-electron microscopy structure of the Hsp90-Cdc37-Cdk4 kinase complex. Surprisingly, the two lobes of Cdk4 are completely separated with the β4-β5 sheet unfolded. Cdc37 mimics part of the kinase N lobe, stabilizing an open kinase conformation by wedging itself between the two lobes. Finally, Hsp90 clamps around the unfolded kinase β5 strand and interacts with exposed N- and C-lobe interfaces, protecting the kinase in a trapped unfolded state. On the basis of this structure and an extensive amount of previously collected data, we propose unifying conceptual and mechanistic models of chaperone-kinase interactions.
History
DepositionFeb 17, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 6, 2016Provider: repository / Type: Initial release
Revision 1.1Apr 19, 2017Group: Other
Revision 1.2Aug 2, 2017Group: Data collection / Category: em_image_scans / em_software / Item: _em_software.image_processing_id / _em_software.name
Revision 2.0Aug 9, 2017Group: Atomic model / Category: atom_site
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z
Revision 2.1Aug 30, 2017Group: Data collection / Category: em_software / Item: _em_software.details / _em_software.name
Revision 2.2Aug 21, 2019Group: Data collection / Derived calculations / Category: em_software / struct_conn
Item: _em_software.name / _struct_conn.pdbx_leaving_atom_flag
Revision 2.3Oct 23, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_conn_type / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn_type.id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

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  • Deposited structure unit
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  • EMDB-3337
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Assembly

Deposited unit
A: HEAT SHOCK PROTEIN HSP 90 BETA
B: HEAT SHOCK PROTEIN HSP 90 BETA
E: HSP90 CO-CHAPERONE CDC37
K: CYCLIN-DEPENDENT KINASE 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)247,4978
Polymers246,4344
Non-polymers1,0634
Water00
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA

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Components

#1: Protein HEAT SHOCK PROTEIN HSP 90 BETA


Mass: 83645.539 Da / Num. of mol.: 2 / Fragment: FULL LENGTH
Source method: isolated from a genetically manipulated source
Details: ATP / Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBACHT / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P08238
#2: Protein HSP90 CO-CHAPERONE CDC37


Mass: 44622.363 Da / Num. of mol.: 1 / Fragment: FULL LENGTH
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBACHT / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: Q16543
#3: Protein CYCLIN-DEPENDENT KINASE 4


Mass: 34520.629 Da / Num. of mol.: 1 / Fragment: FULL LENGTH
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBACHT / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P11802
#4: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
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

ComponentName: COMPLEX OF HUMAN HSP90BETA, HUMAN CDC37 AND HUMAN CDK4
Type: COMPLEX
Buffer solutionName: 20MM TRIS-HCL (PH 7.5), 150 MM NACL, 10 MM KCL, 10 MM MGCL2, 20 MM NA2MOO4, 2MM DTT, 0.085MM DDM
pH: 7.5
Details: 20MM TRIS-HCL (PH 7.5), 150 MM NACL, 10 MM KCL, 10 MM MGCL2, 20 MM NA2MOO4, 2MM DTT, 0.085MM DDM
SpecimenConc.: 0.27 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: HOLEY CARBON
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Details: LIQUID ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS / Date: Nov 25, 2014
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal magnification: 22500 X / Nominal defocus max: 3800 nm / Nominal defocus min: 1400 nm / Cs: 2.7 mm
Image recordingElectron dose: 44 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameCategoryDetails
1MDFFmodel fitting
2Rosettamodel fitting
3Situsmodel fittingCOLORES
4UCSF Chimeramodel fitting
5RELION3D reconstruction
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.9 Å / Num. of particles: 388688 / Actual pixel size: 1.315 Å
Details: SUBMISSION BASED ON EXPERIMENTAL DATA FROM EMDB EMD-3337. (DEPOSITION ID: 14266).
Symmetry type: POINT
RefinementHighest resolution: 3.9 Å
Refinement stepCycle: LAST / Highest resolution: 3.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13048 0 64 0 13112

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