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Open data
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Basic information
Entry | Database: PDB / ID: 5fwl | |||||||||
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Title | Atomic cryoEM structure of Hsp90-Cdc37-Cdk4 complex | |||||||||
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![]() | CHAPERONE / HSP90 / CDC37 / CDK4 / 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 / receptor ligand inhibitor activity / PTK6 Regulates Cell Cycle / HSP90-CDC37 chaperone complex / positive regulation of mitophagy in response to mitochondrial depolarization / negative regulation of proteasomal protein catabolic process / Aryl hydrocarbon receptor signalling / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / 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 / cyclin-dependent kinase / protein kinase regulator activity / cyclin-dependent protein serine/threonine kinase activity / protein folding chaperone complex / cyclin-dependent protein serine/threonine kinase regulator activity / post-transcriptional regulation of gene expression / telomerase holoenzyme complex assembly / Respiratory syncytial virus genome replication / Uptake and function of diphtheria toxin / regulation of cyclin-dependent protein serine/threonine kinase activity / positive regulation of G2/M transition of mitotic cell cycle / 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 / Assembly and release of respiratory syncytial virus (RSV) virions / cyclin-dependent protein kinase holoenzyme complex / regulation of G2/M transition of mitotic cell cycle / dendritic growth cone / regulation of type I interferon-mediated signaling pathway / : / : / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / The NLRP3 inflammasome / Signaling by ERBB2 / telomere maintenance via telomerase / HSF1-dependent transactivation / cyclin binding / response to unfolded protein / chaperone-mediated protein complex assembly / HSF1 activation / bicellular tight junction / Attenuation phase / protein targeting / cellular response to interleukin-4 / RHOBTB2 GTPase cycle / axonal growth cone / Purinergic signaling in leishmaniasis infection / DNA polymerase binding / supramolecular fiber organization / chaperone-mediated protein folding / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / protein folding chaperone / heat shock protein binding / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / nitric-oxide synthase regulator activity / Constitutive Signaling by Overexpressed ERBB2 / ESR-mediated signaling / Signaling by ERBB2 TMD/JMD mutants / Meiotic recombination / peptide binding / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Ubiquitin-dependent degradation of Cyclin D / Signaling by ERBB2 KD Mutants / placenta development / positive regulation of cell differentiation / Transcriptional regulation of granulopoiesis / SCF(Skp2)-mediated degradation of p27/p21 / ATP-dependent protein folding chaperone / kinase binding / Downregulation of ERBB2 signaling / Hsp90 protein binding / DDX58/IFIH1-mediated induction of interferon-alpha/beta / tau protein binding Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 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. | |||||||||
History |
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 609.6 KB | Display | ![]() |
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PDB format | ![]() | 509.1 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 3341MC ![]() 3337C ![]() 3338C ![]() 3339C ![]() 3340C ![]() 3342C ![]() 3343C ![]() 3344C ![]() 5fwkC ![]() 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 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #2: Protein | | Mass: 44622.363 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #3: Protein | | Mass: 34520.629 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #4: Chemical | #5: Chemical | Sequence details | N TERMINAL TAG | |
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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, 150 MM NACL, 10MM KCL, 10MM MGCL2, 20MM NA2MOO4, 2MM DTT, 0.085MM DDM pH: 7.5 Details: 20MM TRIS-HCL, 150 MM NACL, 10MM KCL, 10MM MGCL2, 20MM NA2MOO4, 2MM DTT, 0.085MM DDM |
Specimen | Conc.: 0.27 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Instrument: FEI VITROBOT MARK III / Cryogen name: 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
EM software |
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Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||
3D reconstruction | Resolution: 9 Å / Num. of particles: 45974 / Actual pixel size: 1.315 Å Details: THIS MODEL WAS BUILT BASED ON 5FWK WITH CDK4 N-LOBE RIGID BODY FIT INTO THE EM DENSITY. THE MODEL WAS THEN MINIMIZED IN ROSETTA. SUBMISSION BASED ON EXPERIMENTAL DATA FROM EMDB EMD-3341. (DEPOSITION ID: 14283). Symmetry type: POINT | ||||||||||||
Atomic model building | Protocol: OTHER / Details: METHOD--ROSETTA | ||||||||||||
Refinement | Highest resolution: 9 Å | ||||||||||||
Refinement step | Cycle: LAST / Highest resolution: 9 Å
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