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Open data
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Basic information
Entry | Database: PDB / ID: 5fwk | |||||||||
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Title | Atomic cryoEM structure of Hsp90-Cdc37-Cdk4 complex | |||||||||
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![]() | SIGNALING PROTEIN / HSP90 / CDC37 / CDK4 / CHAPERONE / KINASE / UNFOLDING | |||||||||
Function / homology | ![]() 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 / 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 / aryl hydrocarbon receptor complex / dynein axonemal particle / histone methyltransferase binding / cellular response to phorbol 13-acetate 12-myristate / Transcriptional regulation by RUNX2 / positive regulation of protein localization to cell surface / ATP-dependent protein binding / protein kinase regulator activity / protein folding chaperone complex / cyclin-dependent protein serine/threonine kinase regulator activity / negative regulation of protein metabolic process / positive regulation of tau-protein kinase activity / post-transcriptional regulation of gene expression / telomerase holoenzyme complex assembly / Respiratory syncytial virus genome replication / regulation of cyclin-dependent protein serine/threonine kinase activity / 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 / TPR domain binding / positive regulation of transforming growth factor beta receptor signaling pathway / PTK6 Regulates Cell Cycle / Assembly and release of respiratory syncytial virus (RSV) virions / dendritic growth cone / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / 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 / response to unfolded protein / telomere maintenance via telomerase / chaperone-mediated protein complex assembly / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / HSF1 activation / bicellular tight junction / Attenuation phase / protein targeting / cyclin-dependent kinase / cellular response to interleukin-4 / RHOBTB2 GTPase cycle / cyclin-dependent protein serine/threonine kinase activity / Purinergic signaling in leishmaniasis infection / axonal growth cone / cyclin-dependent protein kinase holoenzyme complex / DNA polymerase binding / supramolecular fiber organization / Signaling by ERBB2 / : / heat shock protein binding / regulation of G2/M transition of mitotic cell cycle / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / positive regulation of G2/M transition of mitotic cell cycle / nitric-oxide synthase regulator activity / cyclin binding / Constitutive Signaling by Overexpressed ERBB2 / ESR-mediated signaling / : / Ubiquitin-dependent degradation of Cyclin D / positive regulation of cell differentiation / ATP-dependent protein folding chaperone / peptide binding / Signaling by ERBB2 TMD/JMD mutants / Hsp90 protein binding / Constitutive Signaling by EGFRvIII / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 ECD mutants / tau protein binding / placenta development / Signaling by ERBB2 KD Mutants / Oncogene Induced Senescence / Regulation of necroptotic cell death / Regulation of actin dynamics for phagocytic cup formation Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å | |||||||||
![]() | Verba, K.A. / Wang, R.Y.R. / Arakawa, A. / Liu, Y. / Yokoyama, S. / Agard, D.A. | |||||||||
![]() | ![]() 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. | |||||||||
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 615.5 KB | Display | ![]() |
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PDB format | ![]() | 524.5 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Summary document | ![]() | 1 MB | Display | ![]() |
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Full document | ![]() | 1.1 MB | Display | |
Data in XML | ![]() | 49.8 KB | Display | |
Data in CIF | ![]() | 76.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 3337MC ![]() 3338C ![]() 3339C ![]() 3340C ![]() 3341C ![]() 3342C ![]() 3343C ![]() 3344C ![]() 5fwlC ![]() 5fwmC ![]() 5fwpC C: citing same article ( M: map data used to model this data |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 83645.539 Da / Num. of mol.: 2 / Fragment: FULL LENGTH Source method: isolated from a genetically manipulated source Details: ATP / Source: (gene. exp.) ![]() ![]() ![]() #2: Protein | | Mass: 44622.363 Da / Num. of mol.: 1 / Fragment: FULL LENGTH Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #3: Protein | | Mass: 34520.629 Da / Num. of mol.: 1 / Fragment: FULL LENGTH Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #4: Chemical | #5: Chemical | |
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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 |
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Sample preparation
Component | Name: COMPLEX OF HUMAN HSP90BETA, HUMAN CDC37 AND HUMAN CDK4 Type: COMPLEX |
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Buffer solution | Name: 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 |
Specimen | Conc.: 0.27 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Details: HOLEY CARBON |
Vitrification | Instrument: 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 |
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Microscopy | Model: FEI TITAN KRIOS / Date: Nov 25, 2014 |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 22500 X / Nominal defocus max: 3800 nm / Nominal defocus min: 1400 nm / Cs: 2.7 mm |
Image recording | Electron dose: 44 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
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Processing
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Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 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 | ||||||||||||||||||||||||
Refinement | Highest resolution: 3.9 Å | ||||||||||||||||||||||||
Refinement step | Cycle: LAST / Highest resolution: 3.9 Å
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