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- PDB-3b25: Hsp90 alpha N-terminal domain in complex with an inhibitor CH4675194 -

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Basic information

Entry
Database: PDB / ID: 3b25
TitleHsp90 alpha N-terminal domain in complex with an inhibitor CH4675194
ComponentsHeat shock protein HSP 90-alpha
KeywordsChaperone/Chaperone inhibitor / Chaperone-Chaperone inhibitor complex
Function / homology
Function and homology information


sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / Scavenging by Class F Receptors / UTP binding / sperm plasma membrane / chaperone-mediated autophagy ...sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / Scavenging by Class F Receptors / UTP binding / sperm plasma membrane / chaperone-mediated autophagy / Rho GDP-dissociation inhibitor binding / Respiratory syncytial virus genome replication / telomerase holoenzyme complex assembly / mitochondrial transport / Uptake and function of diphtheria toxin / protein insertion into mitochondrial outer membrane / 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 / PIWI-interacting RNA (piRNA) biogenesis / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / dendritic growth cone / Sema3A PAK dependent Axon repulsion / protein unfolding / positive regulation of cell size / regulation of protein ubiquitination / HSF1-dependent transactivation / response to unfolded protein / enzyme-substrate adaptor activity / skeletal muscle contraction / regulation of postsynaptic membrane neurotransmitter receptor levels / regulation of protein-containing complex assembly / HSF1 activation / telomere maintenance via telomerase / Attenuation phase / chaperone-mediated protein complex assembly / neurofibrillary tangle assembly / axonal growth cone / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / eNOS activation / nitric oxide metabolic process / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / DNA polymerase binding / positive regulation of defense response to virus by host / response to salt stress / Signaling by ERBB2 / cardiac muscle cell apoptotic process / positive regulation of telomere maintenance via telomerase / endocytic vesicle lumen / positive regulation of cardiac muscle contraction / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / nitric-oxide synthase regulator activity / Recruitment of mitotic centrosome proteins and complexes / Recruitment of NuMA to mitotic centrosomes / activation of innate immune response / Anchoring of the basal body to the plasma membrane / lysosomal lumen / positive regulation of interferon-beta production / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / response to cold / ESR-mediated signaling / Constitutive Signaling by Overexpressed ERBB2 / protein tyrosine kinase binding / AURKA Activation by TPX2 / VEGFR2 mediated vascular permeability / ATP-dependent protein folding chaperone / response to cocaine / Signaling by ERBB2 TMD/JMD mutants / brush border membrane / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / DDX58/IFIH1-mediated induction of interferon-alpha/beta / cellular response to virus / Regulation of actin dynamics for phagocytic cup formation / Regulation of necroptotic cell death / tau protein binding / VEGFA-VEGFR2 Pathway / histone deacetylase binding / positive regulation of protein import into nucleus / Downregulation of ERBB2 signaling / response to estrogen / Chaperone Mediated Autophagy / positive regulation of protein catabolic process / neuron migration / Aggrephagy / disordered domain specific binding / MHC class II protein complex binding / The role of GTSE1 in G2/M progression after G2 checkpoint
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-like ATPase, C-terminal domain / Heat Shock Protein 90 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / 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-like ATPase, C-terminal domain / Heat Shock Protein 90 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / 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-B2K / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.75 Å
AuthorsFukami, T.A. / Ono, N.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Lead generation of heat shock protein 90 inhibitors by a combination of fragment-based approach, virtual screening, and structure-based drug design
Authors: Miura, T. / Fukami, T.A. / Hasegawa, K. / Ono, N. / Suda, A. / Shindo, H. / Yoon, D.O. / Kim, S.J. / Na, Y.J. / Aoki, Y. / Shimma, N. / Tsukuda, T. / Shiratori, Y.
History
DepositionJul 21, 2011Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 14, 2011Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2013Group: Database references
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,0512
Polymers25,7881
Non-polymers2631
Water6,161342
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Heat shock protein HSP 90-alpha
hetero molecules

A: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,1034
Polymers51,5762
Non-polymers5272
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_755-x+2,-y,z1
Buried area1570 Å2
ΔGint-9 kcal/mol
Surface area20010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.788, 91.112, 98.746
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222

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Components

#1: Protein Heat shock protein HSP 90-alpha / Heat shock 86 kDa / HSP 86 / HSP86 / Renal carcinoma antigen NY-REN-38


Mass: 25787.965 Da / Num. of mol.: 1 / Fragment: N-terminal domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1 / Plasmid: pT7-7 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)CP / References: UniProt: P07900
#2: Chemical ChemComp-B2K / 4-Methyl-6-(toluene-4-sulfonyl)-pyrimidin-2-ylamine


Mass: 263.316 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H13N3O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 342 / 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: 2.9 Å3/Da / Density % sol: 57.5 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 18%(w/v) PEG3350, 0.4M MgCl2, 0.1M Tris-Cl, pH 8.0, vapor diffusion, hanging drop, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-6B / Wavelength: 1 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Feb 27, 2004
RadiationMonochromator: double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.75→100 Å / Num. obs: 30759 / % possible obs: 99.8 % / Biso Wilson estimate: 28.09 Å2 / Rmerge(I) obs: 0.069 / Rrim(I) all: 0.069 / Χ2: 1.161 / Net I/σ(I): 11.5
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.75-1.810.41230141.017199.9
1.81-1.890.330561.093199.8
1.89-1.970.21730291.1631100
1.97-2.070.16130691.211100
2.07-2.20.11930581.1961100
2.2-2.380.09530501.1831100
2.38-2.610.07930671.1591100
2.61-2.990.06631091.217199.9
2.99-3.770.0631001.258199.6
3.77-1000.05332071.096198.9

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 0.367 / Cor.coef. Fo:Fc: 0.666
Highest resolutionLowest resolution
Rotation3 Å36.4 Å
Translation3 Å36.4 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
TNTrefinement
PDB_EXTRACT3.006data extraction
BUSTER2.9.6refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→36.4 Å / Cor.coef. Fo:Fc: 0.9517 / Cor.coef. Fo:Fc free: 0.9404 / Occupancy max: 1 / Occupancy min: 1 / SU R Cruickshank DPI: 0.093 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.103 / SU Rfree Blow DPI: 0.097 / SU Rfree Cruickshank DPI: 0.091
RfactorNum. reflection% reflectionSelection details
Rfree0.2028 1548 5.04 %RANDOM
Rwork0.1798 ---
obs0.181 30700 99.83 %-
Displacement parametersBiso max: 115.27 Å2 / Biso mean: 32.9327 Å2 / Biso min: 15.52 Å2
Baniso -1Baniso -2Baniso -3
1-5.333 Å20 Å20 Å2
2---6.5249 Å20 Å2
3---1.1919 Å2
Refine analyzeLuzzati coordinate error obs: 0.188 Å
Refinement stepCycle: LAST / Resolution: 1.75→36.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1645 0 18 342 2005
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d602SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes45HARMONIC2
X-RAY DIFFRACTIONt_gen_planes240HARMONIC5
X-RAY DIFFRACTIONt_it1690HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion232SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2205SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1690HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2281HARMONIC21.07
X-RAY DIFFRACTIONt_omega_torsion3.58
X-RAY DIFFRACTIONt_other_torsion14.66
LS refinement shellResolution: 1.75→1.81 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.2788 149 5.05 %
Rwork0.2086 2802 -
all0.2119 2951 -
obs--99.83 %

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