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- PDB-5lo0: HSP90 WITH indazole derivative -

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Basic information

Entry
Database: PDB / ID: 5lo0
TitleHSP90 WITH indazole derivative
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE
Function / homology
Function and homology information


sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / sperm plasma membrane / chaperone-mediated autophagy ...sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / 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 / 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 / protein import into mitochondrial matrix / dendritic growth cone / TPR domain binding / PIWI-interacting RNA (piRNA) biogenesis / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / protein unfolding / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / positive regulation of cell size / HSF1-dependent transactivation / response to unfolded protein / enzyme-substrate adaptor activity / skeletal muscle contraction / regulation of protein-containing complex assembly / HSF1 activation / Attenuation phase / chaperone-mediated protein complex assembly / telomere maintenance via telomerase / axonal growth cone / neurofibrillary tangle assembly / RHOBTB2 GTPase cycle / regulation of postsynaptic membrane neurotransmitter receptor levels / positive regulation of lamellipodium assembly / nitric oxide metabolic process / eNOS activation / positive regulation of defense response to virus by host / DNA polymerase binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / response to salt stress / positive regulation of telomere maintenance via telomerase / Signaling by ERBB2 / cardiac muscle cell apoptotic process / 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 / Recruitment of mitotic centrosome proteins and complexes / activation of innate immune response / lysosomal lumen / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / positive regulation of interferon-beta production / ESR-mediated signaling / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / protein tyrosine kinase binding / response to cold / Constitutive Signaling by Overexpressed ERBB2 / AURKA Activation by TPX2 / nitric-oxide synthase regulator activity / VEGFR2 mediated vascular permeability / response to cocaine / ATP-dependent protein folding chaperone / brush border membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 KD Mutants / cellular response to virus / Regulation of actin dynamics for phagocytic cup formation / Regulation of necroptotic cell death / positive regulation of protein import into nucleus / VEGFA-VEGFR2 Pathway / response to estrogen / tau protein binding / Downregulation of ERBB2 signaling / histone deacetylase binding / neuron migration / Chaperone Mediated Autophagy / Aggrephagy / positive regulation of nitric oxide biosynthetic process / disordered domain specific binding / MHC class II protein complex binding / positive regulation of protein catabolic process
Similarity search - Function
Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / Histidine kinase-like ATPase, C-terminal domain / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / 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. / Histidine kinase-like ATPase, C-terminal domain / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / 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 superfamily / Ribosomal protein S5 domain 2-type fold / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-70N / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsGraedler, U. / Amaral, M. / Schuetz, D.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Ligand Desolvation Steers On-Rate and Impacts Drug Residence Time of Heat Shock Protein 90 (Hsp90) Inhibitors.
Authors: Schuetz, D.A. / Richter, L. / Amaral, M. / Grandits, M. / Gradler, U. / Musil, D. / Buchstaller, H.P. / Eggenweiler, H.M. / Frech, M. / Ecker, G.F.
History
DepositionAug 8, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 29, 2017Provider: repository / Type: Initial release
Revision 1.1May 23, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jun 6, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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)26,2782
Polymers25,7141
Non-polymers5651
Water84747
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area10230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.593, 91.130, 98.671
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 25713.822 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-70N / [2-azanyl-6-[4,5-bis(fluoranyl)-2-(4-methylpiperazin-1-yl)sulfonyl-phenyl]quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone


Mass: 564.606 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H26F2N6O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 47 / 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: 2.91 Å3/Da / Density % sol: 57.74 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 100 mM BisTris pH 6.5, 250 mM NaF, 21-26% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X1A / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: May 20, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→70 Å / Num. obs: 13667 / % possible obs: 99.4 % / Redundancy: 5 % / Biso Wilson estimate: 63.17 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 25.25
Reflection shellResolution: 2.3→2.44 Å / Rmerge(I) obs: 0.533 / Mean I/σ(I) obs: 3.31 / % possible all: 97.5

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4EEH

4eeh


Resolution: 2.3→45.56 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.932 / Rfactor Rfree error: 0.01 / SU R Cruickshank DPI: 0.226 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.228 / SU Rfree Blow DPI: 0.184 / SU Rfree Cruickshank DPI: 0.185
RfactorNum. reflection% reflectionSelection details
Rfree0.227 683 5 %RANDOM
Rwork0.195 ---
obs0.197 13653 99.7 %-
Displacement parametersBiso mean: 70 Å2
Baniso -1Baniso -2Baniso -3
1-6.1509 Å20 Å20 Å2
2---5.3534 Å20 Å2
3----0.7974 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: 1 / Resolution: 2.3→45.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1627 0 40 52 1719
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.011698HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.112298HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d597SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes46HARMONIC2
X-RAY DIFFRACTIONt_gen_planes241HARMONIC5
X-RAY DIFFRACTIONt_it1698HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.19
X-RAY DIFFRACTIONt_other_torsion17.54
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion229SEMIHARMONIC5
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_contact1972SEMIHARMONIC4
LS refinement shellResolution: 2.3→2.48 Å / Rfactor Rfree error: 0 / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.252 138 5.01 %
Rwork0.198 2619 -
all0.2 2757 -
obs--99.1 %
Refinement TLS params.Method: refined / Origin x: 0.0109 Å / Origin y: -14.8085 Å / Origin z: -20.5202 Å
111213212223313233
T-0.1454 Å20.0148 Å2-0.0214 Å2--0.2191 Å2-0.0207 Å2---0.2145 Å2
L5.8811 °2-1.3918 °2-1.7299 °2-2.4961 °21.5691 °2--4.2204 °2
S0.2245 Å °0.1127 Å °0.3433 Å °-0.2738 Å °-0.0742 Å °-0.1038 Å °-0.3492 Å °-0.0177 Å °-0.1503 Å °
Refinement TLS groupSelection details: { A|* }

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