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- PDB-3eko: Dihydroxylphenyl amides as inhibitors of the Hsp90 molecular chaperone -

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Basic information

Entry
Database: PDB / ID: 3eko
TitleDihydroxylphenyl amides as inhibitors of the Hsp90 molecular chaperone
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE / HSP90 inhibitors / Alternative splicing / ATP-binding / Cytoplasm / Nucleotide-binding / Phosphoprotein / Stress response
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
PHOSPHATE ION / 2-(1H-pyrrol-1-ylcarbonyl)benzene-1,3,5-triol / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsGajiwala, K.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Dihydroxylphenyl amides as inhibitors of the Hsp90 molecular chaperone.
Authors: Kung, P.P. / Funk, L. / Meng, J. / Collins, M. / Zhou, J.Z. / Johnson, M.C. / Ekker, A. / Wang, J. / Mehta, P. / Yin, M.J. / Rodgers, C. / Davies, J.F. / Bayman, E. / Smeal, T. / Maegley, K.A. / Gehring, M.R.
History
DepositionSep 19, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 25, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 21, 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
B: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,6995
Polymers51,1662
Non-polymers5333
Water5,747319
1
A: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,8022
Polymers25,5831
Non-polymers2191
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,8973
Polymers25,5831
Non-polymers3142
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
A: Heat shock protein HSP 90-alpha
hetero molecules

B: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,6995
Polymers51,1662
Non-polymers5333
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_645-x+1,y-1/2,-z+1/21
Buried area2300 Å2
ΔGint-12.1 kcal/mol
Surface area20150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.557, 79.220, 118.177
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
DetailsAuthors state that the two isolated N-terminal domains of HSP90 are most likely monomers in solution.

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Components

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


Mass: 25582.850 Da / Num. of mol.: 2 / Fragment: N-terminal domain: UNP residues 9-225
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Production host: Escherichia coli (E. coli) / References: UniProt: P07900
#2: Chemical ChemComp-PYU / 2-(1H-pyrrol-1-ylcarbonyl)benzene-1,3,5-triol


Mass: 219.193 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H9NO4
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 319 / 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: 2.08 Å3/Da / Density % sol: 40.98 %
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 4.4
Details: 34 % Ethylene glycol, 0.1 M Phoshpate-citrate pH 4.4, 5 mM TCEP, VAPOR DIFFUSION, HANGING DROP, temperature 286K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Aug 3, 2004 / Details: Mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.41→50 Å / Num. all: 119926 / Num. obs: 117734 / % possible obs: 98.1 % / Observed criterion σ(I): 3 / Redundancy: 3.9 % / Biso Wilson estimate: 16.9 Å2 / Rmerge(I) obs: 0.059 / Rsym value: 0.059 / Net I/σ(I): 24.7

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Processing

Software
NameClassification
HKL-2000data collection
CNXrefinement
HKL-2000data reduction
SCALEPACKdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.55→47.37 Å / Rfactor Rfree error: 0.003 / Data cutoff high absF: 334752.45 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.206 5691 4.8 %RANDOM
Rwork0.189 ---
all0.2 81653 --
obs0.19 80044 98.2 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 46.2641 Å2 / ksol: 0.378886 e/Å3
Displacement parametersBiso mean: 17.5 Å2
Baniso -1Baniso -2Baniso -3
1-1.11 Å20 Å20 Å2
2---1.32 Å20 Å2
3---0.21 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.18 Å0.16 Å
Luzzati d res low-5 Å
Luzzati sigma a0.08 Å-0.01 Å
Refinement stepCycle: LAST / Resolution: 1.55→47.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3455 0 37 319 3811
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
X-RAY DIFFRACTIONc_angle_deg0.9
X-RAY DIFFRACTIONc_dihedral_angle_d19.7
X-RAY DIFFRACTIONc_improper_angle_d0.59
X-RAY DIFFRACTIONc_mcbond_it1.141.5
X-RAY DIFFRACTIONc_mcangle_it1.782
X-RAY DIFFRACTIONc_scbond_it2.142
X-RAY DIFFRACTIONc_scangle_it3.152.5
LS refinement shellResolution: 1.55→1.65 Å / Rfactor Rfree error: 0.007 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.223 949 5 %
Rwork0.19 18111 -
obs--95.5 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.parprotein.top
X-RAY DIFFRACTION2dna-rna_rep.pardna-rna.top
X-RAY DIFFRACTION3water_rep.parwater.top
X-RAY DIFFRACTION4ion.paramion.top
X-RAY DIFFRACTION5lig.paramlig.top

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