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- PDB-2h55: Structure of human Hsp90-alpha bound to the potent water soluble ... -

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Basic information

Entry
Database: PDB / ID: 2h55
TitleStructure of human Hsp90-alpha bound to the potent water soluble inhibitor PU-DZ8
ComponentsHeat shock protein HSP 90-alpha 4
KeywordsCHAPERONE / HSP90 / GRP94 / purine / PU3 / H64 / H71 / DZ8
Function / homology
Function and homology information


regulation of protein localization => GO:0032880 / positive regulation of protein catabolic process => GO:0045732 / ciliary basal body-plasma membrane docking / central nervous system neuron axonogenesis / neutrophil degranulation / ERBB2 signaling pathway / axon extension / sperm mitochondrial sheath / dATP binding / Scavenging by Class F Receptors ...regulation of protein localization => GO:0032880 / positive regulation of protein catabolic process => GO:0045732 / ciliary basal body-plasma membrane docking / central nervous system neuron axonogenesis / neutrophil degranulation / ERBB2 signaling pathway / axon extension / sperm mitochondrial sheath / dATP binding / Scavenging by Class F Receptors / sulfonylurea receptor binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / UTP binding / sperm plasma membrane / positive regulation of tau-protein kinase activity / protein insertion into mitochondrial outer membrane / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / regulation of nitric-oxide synthase activity / establishment of cell polarity / Uptake and function of diphtheria toxin / Rho GDP-dissociation inhibitor binding / mitochondrial transport / 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 / Fc-gamma receptor signaling pathway involved in phagocytosis / PIWI-interacting RNA (piRNA) biogenesis / TPR domain binding / non-chaperonin molecular chaperone ATPase / regulation of postsynaptic membrane neurotransmitter receptor levels / dendritic growth cone / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / skeletal muscle contraction / HSF1-dependent transactivation / positive regulation of cell size / response to unfolded protein / telomere maintenance via telomerase / chaperone-mediated protein complex assembly / protein unfolding / HSF1 activation / regulation of protein-containing complex assembly / Attenuation phase / RHOBTB2 GTPase cycle / vascular endothelial growth factor receptor signaling pathway / eNOS activation / positive regulation of lamellipodium assembly / axonal growth cone / DNA polymerase binding / regulation of cellular response to heat / protein folding chaperone / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / positive regulation of telomerase activity / positive regulation of cardiac muscle contraction / Signaling by ERBB2 / cardiac muscle cell apoptotic process / positive regulation of defense response to virus by host / endocytic vesicle lumen / Recruitment of NuMA to mitotic centrosomes / response to salt stress / Anchoring of the basal body to the plasma membrane / regulation of G2/M transition of mitotic cell cycle / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / activation of innate immune response / nitric-oxide synthase regulator activity / positive regulation of interferon-beta production / viral process / response to cold / Constitutive Signaling by Overexpressed ERBB2 / AURKA Activation by TPX2 / lysosomal lumen / ESR-mediated signaling / protein tyrosine kinase binding / receptor-mediated endocytosis / VEGFR2 mediated vascular permeability / response to cocaine / brush border membrane / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / neuron migration / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / tau protein binding / Signaling by ERBB2 KD Mutants / Regulation of necroptotic cell death / Regulation of actin dynamics for phagocytic cup formation
Similarity search - Function
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 / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase ...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 / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / 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 / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-DZ8 / Heat shock protein HSP 90-alpha / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsImmormino, R.M. / Gewirth, D.T.
CitationJournal: J.Med.Chem. / Year: 2006
Title: Structural and quantum chemical studies of 8-aryl-sulfanyl adenine class Hsp90 inhibitors.
Authors: Immormino, R.M. / Kang, Y. / Chiosis, G. / Gewirth, D.T.
History
DepositionMay 25, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 3, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Heat shock protein HSP 90-alpha 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,2852
Polymers28,7731
Non-polymers5121
Water5,675315
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.735, 91.035, 98.534
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
DetailsThe asymmetrict unit comprises the assumed biological molecule

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Components

#1: Protein Heat shock protein HSP 90-alpha 4 / HSP90 PROTEIN


Mass: 28773.145 Da / Num. of mol.: 1 / Fragment: N-terminal Domain Residues 1-236
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSPCA / Plasmid: PET-15b / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q5CAQ6, UniProt: P07900*PLUS
#2: Chemical ChemComp-DZ8 / 2-FLUORO-8-[(6-IODO-1,3-BENZODIOXOL-5-YL)METHYL]-9-[3-(ISOPROPYLAMINO)PROPYL]-9H-PURIN-6-AMINE


Mass: 512.320 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H22FIN6O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 315 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.6 Å3/Da / Density % sol: 52.69 %
Description: THE STRUCTURE FACTOR FILE contains FRIEDEL PAIRS.
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 10-12% PEG-2KMME, .1-.3M MgCl2, .1 M NaCacodylate 5 molar excess of PU-DZ8, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Apr 28, 2006 / Details: Osmic Mirrors
RadiationMonochromator: Copper K-alpha / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. all: 39220 / Num. obs: 35715 / % possible obs: 90.3 % / Observed criterion σ(F): -3 / Redundancy: 2.1 % / Biso Wilson estimate: 24.3 Å2 / Rsym value: 0.059 / Net I/σ(I): 23.67
Reflection shellResolution: 2→2.07 Å / Redundancy: 2 % / Mean I/σ(I) obs: 3.28 / Num. unique all: 3583 / Rsym value: 0.261 / % possible all: 90

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Processing

Software
NameVersionClassification
CNS1.1refinement
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 2FWZ

2fwz


Resolution: 2→29 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 446600.52 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Details: THE FRIEDEL PAIRS WERE USED FOR phasing.
RfactorNum. reflection% reflectionSelection details
Rfree0.213 3066 8.9 %RANDOM
Rwork0.166 ---
all-39220 --
obs-34351 87.6 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 52.2717 Å2 / ksol: 0.31893 e/Å3
Displacement parametersBiso mean: 33.5 Å2
Baniso -1Baniso -2Baniso -3
1--1.46 Å20 Å20 Å2
2---0.16 Å20 Å2
3---1.61 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.23 Å0.19 Å
Luzzati d res low-5 Å
Luzzati sigma a0.07 Å0.15 Å
Refinement stepCycle: LAST / Resolution: 2→29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1716 0 29 315 2060
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d22.5
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d1.91
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.261.5
X-RAY DIFFRACTIONc_mcangle_it1.992
X-RAY DIFFRACTIONc_scbond_it1.992
X-RAY DIFFRACTIONc_scangle_it2.932.5
LS refinement shellResolution: 2→2.13 Å / Rfactor Rfree error: 0.01 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.235 502 9.2 %
Rwork0.216 4963 -
obs--83.2 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3dz8_param.paramdz8_top.top

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