|Entry||Database: PDB / ID: 5fwm|
|Title||Atomic cryoEM structure of Hsp90-Cdc37-Cdk4 complex|
|Keywords||CHAPERONE / HSP90 / CDC37 / CDK4 / KINASE / UNFOLDING|
|Function / homology||Cdc37 N terminal kinase binding / SCF(Skp2)-mediated degradation of p27/p21 / Protein kinases ATP-binding region signature. / Serine/Threonine protein kinases active-site signature. / Heat shock hsp90 proteins family signature. / Protein kinase domain profile. / Signaling by ERBB2 / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Regulation of actin dynamics for phagocytic cup formation / Protein kinase domain ...Cdc37 N terminal kinase binding / SCF(Skp2)-mediated degradation of p27/p21 / Protein kinases ATP-binding region signature. / Serine/Threonine protein kinases active-site signature. / Heat shock hsp90 proteins family signature. / Protein kinase domain profile. / Signaling by ERBB2 / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Regulation of actin dynamics for phagocytic cup formation / Protein kinase domain / Oxidative Stress Induced Senescence / Cdc37 C terminal domain / Oncogene Induced Senescence / RMTs methylate histone arginines / HSP90 chaperone cycle for steroid hormone receptors (SHR) / HSF1 activation / Attenuation phase / Cdc37 Hsp90 binding domain / Heat shock protein Hsp90 family / Transcriptional regulation of white adipocyte differentiation / Ribosomal protein S5 domain 2-type fold / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Hsp90 protein / Protein kinase domain / Cdc37, Hsp90-binding domain superfamily / HSP90, C-terminal domain / Histidine kinase/HSP90-like ATPase superfamily / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90, conserved site / Histidine kinase/HSP90-like ATPase / Protein kinase, ATP binding site / Cdc37, Hsp90 binding / Cdc37, C-terminal / Cdc37, N-terminal domain / Protein kinase-like domain superfamily / Serine/threonine-protein kinase, active site / Cdc37 / HSF1-dependent transactivation / Senescence-Associated Secretory Phenotype (SASP) / Transcriptional regulation by RUNX2 / Cyclin D associated events in G1 / Estrogen-dependent gene expression / Downregulation of ERBB2 signaling / Constitutive Signaling by EGFRvIII / ESR-mediated signaling / The role of GTSE1 in G2/M progression after G2 checkpoint / PTK6 Regulates Cell Cycle / Meiotic recombination / The NLRP3 inflammasome / Uptake and function of diphtheria toxin / Aryl hydrocarbon receptor signalling / Neutrophil degranulation / Ubiquitin-dependent degradation of Cyclin D1 / Sema3A PAK dependent Axon repulsion / cellular response to phorbol 13-acetate 12-myristate / negative regulation of transforming growth factor beta activation / ooplasm / regulation of lipid biosynthetic process / sperm head plasma membrane / cyclin D2-CDK4 complex / sulfonylurea receptor binding / regulation of lipid catabolic process / positive regulation of cyclin-dependent protein kinase activity / aryl hydrocarbon receptor complex / HSP90-CDC37 chaperone complex / dATP binding / CTP binding / positive regulation of mitophagy in response to mitochondrial depolarization / cellular response to ionomycin / negative regulation of proteasomal protein catabolic process / histone methyltransferase binding / negative regulation of complement-dependent cytotoxicity / negative regulation of protein metabolic process / UTP binding / protein kinase regulator activity / positive regulation of protein localization to cell surface / regulation of insulin receptor signaling pathway / chaperone complex / positive regulation of cell size / posttranscriptional regulation of gene expression / ATP-dependent protein binding / response to salt stress / regulation of interferon-gamma-mediated signaling pathway / cyclin-dependent protein serine/threonine kinase regulator activity / supramolecular fiber organization / lens development in camera-type eye / brush border membrane / adipose tissue development / positive regulation of transforming growth factor beta receptor signaling pathway / response to testosterone / telomerase holoenzyme complex assembly / regulation of cyclin-dependent protein serine/threonine kinase activity / protein targeting / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / dendritic growth cone / TPR domain binding / cellular response to interleukin-4 / regulation of type I interferon-mediated signaling pathway / negative regulation of cell cycle arrest / central nervous system neuron axonogenesis|
Function and homology information
|Specimen source||HOMO SAPIENS (human)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / 8 Å resolution|
|Authors||Verba, K.A. / Wang, R.Y.R. / Arakawa, A. / Liu, Y. / Yokoyama, S. / Agard, D.A.|
|Citation||Journal: 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.
SummaryFull reportAbout validation report
|Date||Deposition: Feb 18, 2016 / Release: Jul 6, 2016|
|Structure viewer||Molecule: |
Downloads & links
A: HEAT SHOCK PROTEIN HSP 90 BETA
B: HEAT SHOCK PROTEIN HSP 90 BETA
E: HSP90 CO-CHAPERONE CDC37
K: CYCLIN-DEPENDENT KINASE 4
Mass: 83645.539 Da / Num. of mol.: 2 / Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid name: PFASTBACHT / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P08238
Mass: 44622.363 Da / Num. of mol.: 1 / Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid name: PFASTBACHT / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: Q16543
Mass: 34520.629 Da / Num. of mol.: 1 / Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid name: PFASTBACHT / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P11802
Mass: 507.181 Da / Num. of mol.: 2 / Formula: C10H16N5O13P3 / Adenosine triphosphate / Comment: ATP (energy-carrying molecule) *YM
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / Reconstruction method: single particle reconstruction|
|Component||Name: COMPLEX OF HUMAN HSP90BETA, HUMAN CDC37 AND HUMAN CDK4|
|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|
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|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Microscope model: FEI TITAN KRIOS / Date: Nov 25, 2014|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 22500 / 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)|
|Symmetry||Point symmetry: C1|
|3D reconstruction||Resolution: 8 Å / Number of particles: 61981 / Actual pixel size: 1.315|
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-3342. (DEPOSITION ID: 14285).
Symmetry type: POINT
|Atomic model building||Details: METHOD--ROSETTA / Ref protocol: OTHER|
|Least-squares process||Highest resolution: 8 Å|
|Refine hist #LAST||Highest resolution: 8 Å|
|Number of atoms included #LAST||Protein: 14743 / Nucleic acid: 0 / Ligand: 64 / Solvent: 0 / Total: 14807|
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