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- EMDB-23213: Cryo-EM structure of Hsp90:FKBP51:p23 closed-state complex -

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Entry
Database: EMDB / ID: EMD-23213
TitleCryo-EM structure of Hsp90:FKBP51:p23 closed-state complex
Map dataCryo-EM structure of Hsp90:FKBP51:p23 closed-state complex
Sample
  • Complex: Hsp90:FKBP51:p23 closed-state complex
    • Protein or peptide: Peptidyl-prolyl cis-trans isomerase FKBP5
    • Protein or peptide: Heat shock protein HSP 90-alpha
    • Protein or peptide: Prostaglandin E synthase 3
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER
KeywordsISOMERASE-CHAPERONE complex
Function / homology
Function and homology information


prostaglandin-E synthase / prostaglandin-E synthase activity / Aryl hydrocarbon receptor signalling / telomerase activity / prostanoid biosynthetic process / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / cyclooxygenase pathway / prostaglandin biosynthetic process / Modulation of host responses by IFN-stimulated genes / telomerase holoenzyme complex ...prostaglandin-E synthase / prostaglandin-E synthase activity / Aryl hydrocarbon receptor signalling / telomerase activity / prostanoid biosynthetic process / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / cyclooxygenase pathway / prostaglandin biosynthetic process / Modulation of host responses by IFN-stimulated genes / telomerase holoenzyme complex / sperm plasma membrane / sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly / UTP binding / mitochondrial transport / dATP binding / telomerase holoenzyme complex assembly / chaperone-mediated autophagy / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / FK506 binding / 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 / Uptake and function of diphtheria toxin / positive regulation of cell size / dendritic growth cone / protein import into mitochondrial matrix / TPR domain binding / PIWI-interacting RNA (piRNA) biogenesis / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / response to salt stress / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / response to unfolded protein / HSF1-dependent transactivation / cardiac muscle cell apoptotic process / regulation of protein-containing complex assembly / protein folding chaperone complex / Attenuation phase / HSF1 activation / enzyme-substrate adaptor activity / chaperone-mediated protein complex assembly / axonal growth cone / neurofibrillary tangle assembly / regulation of postsynaptic membrane neurotransmitter receptor levels / telomere maintenance via telomerase / positive regulation of lamellipodium assembly / RHOBTB2 GTPase cycle / Dengue virus activates/modulates innate and adaptive immune responses / nitric oxide metabolic process / protein unfolding / MECP2 regulates neuronal receptors and channels / positive regulation of defense response to virus by host / skeletal muscle contraction / Signaling by ERBB2 / eNOS activation / response to cold / heat shock protein binding / positive regulation of telomere maintenance via telomerase / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / endocytic vesicle lumen / DNA polymerase binding / positive regulation of cardiac muscle contraction / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / lysosomal lumen / Recruitment of NuMA to mitotic centrosomes / ESR-mediated signaling / Anchoring of the basal body to the plasma membrane / activation of innate immune response / positive regulation of interferon-beta production / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / telomere maintenance / AURKA Activation by TPX2 / protein tyrosine kinase binding / Constitutive Signaling by Overexpressed ERBB2 / nitric-oxide synthase regulator activity / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / ATP-dependent protein folding chaperone / response to cocaine / VEGFR2 mediated vascular permeability / peptidylprolyl isomerase / brush border membrane / peptidyl-prolyl cis-trans isomerase activity / : / cellular response to virus
Similarity search - Function
Co-chaperone protein p23-like / CS domain / CS domain / CS domain profile. / : / HSP20-like chaperone / Tetratricopeptide repeat / Tetratricopeptide repeat / Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. ...Co-chaperone protein p23-like / CS domain / CS domain / CS domain profile. / : / HSP20-like chaperone / Tetratricopeptide repeat / Tetratricopeptide repeat / 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-, DNA gyrase B-, and HSP90-like ATPase / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / TPR repeat region circular profile. / Peptidyl-prolyl cis-trans isomerase domain superfamily / TPR repeat profile. / Tetratricopeptide repeats / Tetratricopeptide repeat / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / Tetratricopeptide-like helical domain superfamily / Ribosomal protein S5 domain 2-type fold
Similarity search - Domain/homology
Heat shock protein HSP 90-alpha / Peptidyl-prolyl cis-trans isomerase FKBP5 / Prostaglandin E synthase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsLee K / Thwin AC
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG002132 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)AG068125 United States
CitationJournal: Mol Cell / Year: 2021
Title: The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state.
Authors: Kanghyun Lee / Aye C Thwin / Cory M Nadel / Eric Tse / Stephanie N Gates / Jason E Gestwicki / Daniel R Southworth /
Abstract: The Hsp90 chaperone promotes folding and activation of hundreds of client proteins in the cell through an ATP-dependent conformational cycle guided by distinct cochaperone regulators. The FKBP51 ...The Hsp90 chaperone promotes folding and activation of hundreds of client proteins in the cell through an ATP-dependent conformational cycle guided by distinct cochaperone regulators. The FKBP51 immunophilin binds Hsp90 with its tetratricopeptide repeat (TPR) domain and catalyzes peptidyl-prolyl isomerase (PPIase) activity during folding of kinases, nuclear receptors, and tau. Here we determined the cryoelectron microscopy (cryo-EM) structure of the human Hsp90:FKBP51:p23 complex to 3.3 Å, which, together with mutagenesis and crosslinking analyses, reveals the basis for cochaperone binding to Hsp90 during client maturation. A helix extension in the TPR functions as a key recognition element, interacting across the Hsp90 C-terminal dimer interface presented in the closed, ATP conformation. The PPIase domain is positioned along the middle domain, adjacent to Hsp90 client binding sites, whereas a single p23 makes stabilizing interactions with the N-terminal dimer. With this architecture, FKBP51 is positioned to act on specific client residues presented during Hsp90-catalyzed remodeling.
History
DepositionDec 28, 2020-
Header (metadata) releaseAug 25, 2021-
Map releaseAug 25, 2021-
UpdateMay 29, 2024-
Current statusMay 29, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.27
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.27
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7l7i
  • Surface level: 0.27
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23213.png

Downloads & links

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Map

FileDownload / File: emd_23213.map.gz / Format: CCP4 / Size: 190.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of Hsp90:FKBP51:p23 closed-state complex
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.81 Å/pix.
x 368 pix.
= 299.552 Å		0.81 Å/pix.
x 368 pix.
= 299.552 Å		0.81 Å/pix.
x 368 pix.
= 299.552 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.814 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.25 / Movie #1: 0.27
Minimum - Maximum-1.0384736 - 2.3597062
Average (Standard dev.)0.001707026 (±0.053198084)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions368368368
Spacing368368368
CellA=B=C: 299.552 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8140.8140.814
M x/y/z368368368
origin x/y/z0.0000.0000.000
length x/y/z299.552299.552299.552
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS368368368
D min/max/mean-1.0382.3600.002

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Supplemental data

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Sample components

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Entire : Hsp90:FKBP51:p23 closed-state complex

EntireName: Hsp90:FKBP51:p23 closed-state complex
Components
  • Complex: Hsp90:FKBP51:p23 closed-state complex
    • Protein or peptide: Peptidyl-prolyl cis-trans isomerase FKBP5
    • Protein or peptide: Heat shock protein HSP 90-alpha
    • Protein or peptide: Prostaglandin E synthase 3
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER

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Supramolecule #1: Hsp90:FKBP51:p23 closed-state complex

SupramoleculeName: Hsp90:FKBP51:p23 closed-state complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Peptidyl-prolyl cis-trans isomerase FKBP5

MacromoleculeName: Peptidyl-prolyl cis-trans isomerase FKBP5 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: peptidylprolyl isomerase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 51.290191 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MTTDEGAKNN EESPTATVAE QGEDITSKKD RGVLKIVKRV GNGEETPMIG DKVYVHYKGK LSNGKKFDSS HDRNEPFVFS LGKGQVIKA WDIGVATMKK GEICHLLCKP EYAYGSAGSL PKIPSNATLF FEIELLDFKG EDLFEDGGII RRTKRKGEGY S NPNEGATV ...String:
MTTDEGAKNN EESPTATVAE QGEDITSKKD RGVLKIVKRV GNGEETPMIG DKVYVHYKGK LSNGKKFDSS HDRNEPFVFS LGKGQVIKA WDIGVATMKK GEICHLLCKP EYAYGSAGSL PKIPSNATLF FEIELLDFKG EDLFEDGGII RRTKRKGEGY S NPNEGATV EIHLEGRCGG RMFDCRDVAF TVGEGEDHDI PIGIDKALEK MQREEQCILY LGPRYGFGEA GKPKFGIEPN AE LIYEVTL KSFEKAKESW EMDTKEKLEQ AAIVKEKGTV YFKGGKYMQA VIQYGKIVSW LEMEYGLSEK ESKASESFLL AAF LNLAMC YLKLREYTKA VECCDKALGL DSANEKGLYR RGEAQLLMNE FESAKGDFEK VLEVNPQNKA ARLQISMCQK KAKE HNERD RRIYANMFKK FAEQDAKEEA NKAMGKKTSE GVTNEKGTDS QAMEEEKPEG HV

UniProtKB: Peptidyl-prolyl cis-trans isomerase FKBP5

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Macromolecule #2: Heat shock protein HSP 90-alpha

MacromoleculeName: Heat shock protein HSP 90-alpha / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 84.781727 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MPEETQTQDQ PMEEEEVETF AFQAEIAQLM SLIINTFYSN KEIFLRELIS NSSDALDKIR YESLTDPSKL DSGKELHINL IPNKQDRTL TIVDTGIGMT KADLINNLGT IAKSGTKAFM EALQAGADIS MIGQFGVGFY SAYLVAEKVT VITKHNDDEQ Y AWESSAGG ...String:
MPEETQTQDQ PMEEEEVETF AFQAEIAQLM SLIINTFYSN KEIFLRELIS NSSDALDKIR YESLTDPSKL DSGKELHINL IPNKQDRTL TIVDTGIGMT KADLINNLGT IAKSGTKAFM EALQAGADIS MIGQFGVGFY SAYLVAEKVT VITKHNDDEQ Y AWESSAGG SFTVRTDTGE PMGRGTKVIL HLKEDQTEYL EERRIKEIVK KHSQFIGYPI TLFVEKERDK EVSDDEAEEK ED KEEEKEK EEKESEDKPE IEDVGSDEEE EKKDGDKKKK KKIKEKYIDQ EELNKTKPIW TRNPDDITNE EYGEFYKSLT NDW EDHLAV KHFSVEGQLE FRALLFVPRR APFDLFENRK KKNNIKLYVR RVFIMDNCEE LIPEYLNFIR GVVDSEDLPL NISR EMLQQ SKILKVIRKN LVKKCLELFT ELAEDKENYK KFYEQFSKNI KLGIHEDSQN RKKLSELLRY YTSASGDEMV SLKDY CTRM KENQKHIYYI TGETKDQVAN SAFVERLRKH GLEVIYMIEP IDEYCVQQLK EFEGKTLVSV TKEGLELPED EEEKKK QEE KKTKFENLCK IMKDILEKKV EKVVVSNRLV TSPCCIVTST YGWTANMERI MKAQALRDNS TMGYMAAKKH LEINPDH SI IETLRQKAEA DKNDKSVKDL VILLYETALL SSGFSLEDPQ THANRIYRMI KLGLGIDEDD PTADDTSAAV TEEMPPLE G DDDTSRMEEV D

UniProtKB: Heat shock protein HSP 90-alpha

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Macromolecule #3: Prostaglandin E synthase 3

MacromoleculeName: Prostaglandin E synthase 3 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: prostaglandin-E synthase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.720395 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MQPASAKWYD RRDYVFIEFC VEDSKDVNVN FEKSKLTFSC LGGSDNFKHL NEIDLFHCID PNDSKHKRTD RSILCCLRKG ESGQSWPRL TKERAKLNWL SVDFNNWKDW EDDSDEDMSN FDRFSEMMNN MGGDEDVDLP EVDGADDDSQ DSDDEKMPDL E

UniProtKB: Prostaglandin E synthase 3

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Macromolecule #4: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER

MacromoleculeName: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / type: ligand / ID: 4 / Number of copies: 2 / Formula: ANP
Molecular weightTheoretical: 506.196 Da
Chemical component information

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recording#0 - Image recording ID: 1 / #0 - Film or detector model: GATAN K2 SUMMIT (4k x 4k) / #0 - Average electron dose: 70.0 e/Å2 / #1 - Image recording ID: 2 / #1 - Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / #1 - Average electron dose: 66.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Image recording ID1
Particle selectionNumber selected: 576169
Startup model#0 - Type of model: PDB ENTRY
#0 - PDB model - PDB ID:

5fwk


#1 - Type of model: PDB ENTRY
#1 - PDB model - PDB ID:

5njx

Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2) / Number images used: 121882
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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