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- PDB-6ey8: Estimation of relative drug-target residence times by random acce... -

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Basic information

Entry
Database: PDB / ID: 6ey8
TitleEstimation of relative drug-target residence times by random acceleration molecular dynamics simulation
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE / CHAPERONE PROTEIN / ATP BINDING
Function / homology
Function and homology information


positive regulation of tau-protein kinase activity / 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 / 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 / protein insertion into mitochondrial outer membrane / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / Uptake and function of diphtheria toxin / 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 / PIWI-interacting RNA (piRNA) biogenesis / TPR domain binding / non-chaperonin molecular chaperone ATPase / Assembly and release of respiratory syncytial virus (RSV) virions / dendritic growth cone / regulation of postsynaptic membrane neurotransmitter receptor levels / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / skeletal muscle contraction / telomere maintenance via telomerase / protein unfolding / HSF1-dependent transactivation / response to unfolded protein / positive regulation of cell size / chaperone-mediated protein complex assembly / regulation of protein-containing complex assembly / HSF1 activation / Attenuation phase / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / axonal growth cone / eNOS activation / DNA polymerase binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / positive regulation of defense response to virus by host / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / Signaling by ERBB2 / response to salt stress / cardiac muscle cell apoptotic process / endocytic vesicle lumen / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / positive regulation of cardiac muscle contraction / activation of innate immune response / nitric-oxide synthase regulator activity / positive regulation of interferon-beta production / response to cold / AURKA Activation by TPX2 / lysosomal lumen / Constitutive Signaling by Overexpressed ERBB2 / ESR-mediated signaling / protein tyrosine kinase binding / VEGFR2 mediated vascular permeability / response to cocaine / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / brush border membrane / neuron migration / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 KD Mutants / tau protein binding / Regulation of necroptotic cell death / cellular response to virus / Regulation of actin dynamics for phagocytic cup formation / Downregulation of ERBB2 signaling / VEGFA-VEGFR2 Pathway / histone deacetylase binding / positive regulation of protein import into nucleus / Aggrephagy / Chaperone Mediated Autophagy / response to estrogen / positive regulation of protein catabolic process / The role of GTSE1 in G2/M progression after G2 checkpoint / disordered domain specific binding / positive regulation of nitric oxide biosynthetic process / Regulation of PLK1 Activity at G2/M Transition / unfolded protein binding / melanosome
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-C4T / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2.16 Å
AuthorsMusil, D. / Lehmann, M. / Buchstaller, H.-P.
CitationJournal: J Chem Theory Comput / Year: 2018
Title: Estimation of Drug-Target Residence Times by tau-Random Acceleration Molecular Dynamics Simulations.
Authors: Kokh, D.B. / Amaral, M. / Bomke, J. / Gradler, U. / Musil, D. / Buchstaller, H.P. / Dreyer, M.K. / Frech, M. / Lowinski, M. / Vallee, F. / Bianciotto, M. / Rak, A. / Wade, R.C.
History
DepositionNov 11, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 30, 2018Provider: repository / Type: Initial release
Revision 1.1Jul 18, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)27,1824
Polymers26,6021
Non-polymers5803
Water2,810156
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area410 Å2
ΔGint-10 kcal/mol
Surface area10350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.405, 90.039, 98.218
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 / HSP86 / Lipopolysaccharide-associated protein 2 / LPS-associated protein 2 / ...Heat shock 86 kDa / HSP86 / Lipopolysaccharide-associated protein 2 / LPS-associated protein 2 / Renal carcinoma antigen NY-REN-38


Mass: 26601.773 Da / Num. of mol.: 1
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-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-C4T / ~{N}-[(4-chlorophenyl)methyl]-~{N}-methyl-6-oxidanyl-3-(phenylmethyl)-1~{H}-indazole-5-carboxamide


Mass: 405.877 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H20ClN3O2
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 156 / 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: 3.22 Å3/Da / Density % sol: 61.81 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1 M Na-cacodylateNa, pH 6.5 30% PEG8000 0.2 M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Oct 10, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.16→50 Å / Num. obs: 16071 / % possible obs: 98.4 % / Redundancy: 2.9 % / Biso Wilson estimate: 46.07 Å2 / Rmerge(I) obs: 0.068 / Χ2: 1.061 / Net I/σ(I): 9.2
Reflection shellResolution: 2.16→2.25 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.662 / Num. unique obs: 1520 / Χ2: 1.067 / % possible all: 94.2

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.22data extraction
DENZOdata reduction
MOLREPphasing
RefinementResolution: 2.16→33.19 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.93 / SU R Cruickshank DPI: 0.183 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.196 / SU Rfree Blow DPI: 0.179 / SU Rfree Cruickshank DPI: 0.174
RfactorNum. reflection% reflectionSelection details
Rfree0.237 806 5.02 %RANDOM
Rwork0.184 ---
obs0.186 16071 98 %-
Displacement parametersBiso max: 122.36 Å2 / Biso mean: 46.51 Å2 / Biso min: 27.2 Å2
Baniso -1Baniso -2Baniso -3
1-1.9349 Å20 Å20 Å2
2---3.0971 Å20 Å2
3---1.1622 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: final / Resolution: 2.16→33.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1627 0 38 156 1821
Biso mean--47.84 51.92 -
Num. residues----207
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d603SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes47HARMONIC2
X-RAY DIFFRACTIONt_gen_planes242HARMONIC5
X-RAY DIFFRACTIONt_it1702HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion230SEMIHARMONIC5
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_contact2065SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1702HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2299HARMONIC21.1
X-RAY DIFFRACTIONt_omega_torsion3.44
X-RAY DIFFRACTIONt_other_torsion17.07
LS refinement shellResolution: 2.16→2.31 Å / Rfactor Rfree error: 0 / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.2801 129 4.7 %
Rwork0.2247 2616 -
all0.2272 2745 -
obs--94.07 %

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