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- PDB-4o09: Identification of novel HSP90 / isoform selective inhibitors usin... -

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Basic information

Entry
Database: PDB / ID: 4o09
TitleIdentification of novel HSP90 / isoform selective inhibitors using structure-based drug design. Demonstration of potential utility in treating CNS disorders such as Huntington s disease
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE/CHAPERONE INHIBITOR / chaperone / CHAPERONE-CHAPERONE INHIBITOR complex
Function / homology
Function and homology information


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 / positive regulation of tau-protein kinase activity / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / protein insertion into mitochondrial outer membrane / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / 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 / mitochondrial transport / 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 / HSF1-dependent transactivation / positive regulation of cell size / telomere maintenance via telomerase / response to unfolded protein / protein unfolding / chaperone-mediated protein complex assembly / HSF1 activation / regulation of protein-containing complex assembly / Attenuation phase / RHOBTB2 GTPase cycle / eNOS activation / axonal growth cone / positive regulation of lamellipodium assembly / 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 / cardiac muscle cell apoptotic process / endocytic vesicle lumen / Recruitment of NuMA to mitotic centrosomes / response to salt stress / positive regulation of cardiac muscle contraction / Anchoring of the basal body to the plasma membrane / 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 / response to cold / Constitutive Signaling by Overexpressed ERBB2 / AURKA Activation by TPX2 / lysosomal lumen / ESR-mediated signaling / protein tyrosine kinase binding / VEGFR2 mediated vascular permeability / response to cocaine / brush border membrane / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / neuron migration / Constitutive Signaling by EGFRvIII / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 ECD mutants / tau protein binding / Signaling by ERBB2 KD Mutants / 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 / Aggrephagy / Chaperone Mediated Autophagy / positive regulation of protein import into nucleus / response to estrogen / positive regulation of protein catabolic process / The role of GTSE1 in G2/M progression after G2 checkpoint / regulation of protein localization / disordered domain specific binding / Regulation of PLK1 Activity at G2/M Transition / positive regulation of nitric oxide biosynthetic process / unfolded protein binding
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-2R6 / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.96 Å
AuthorsZuccola, H.J. / Ernst, J.T.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Identification of Novel HSP90 alpha / beta Isoform Selective Inhibitors Using Structure-Based Drug Design. Demonstration of Potential Utility in Treating CNS Disorders such as Huntington's Disease.
Authors: Ernst, J.T. / Neubert, T. / Liu, M. / Sperry, S. / Zuccola, H. / Turnbull, A. / Fleck, B. / Kargo, W. / Woody, L. / Chiang, P. / Tran, D. / Chen, W. / Snyder, P. / Alcacio, T. / Nezami, A. / ...Authors: Ernst, J.T. / Neubert, T. / Liu, M. / Sperry, S. / Zuccola, H. / Turnbull, A. / Fleck, B. / Kargo, W. / Woody, L. / Chiang, P. / Tran, D. / Chen, W. / Snyder, P. / Alcacio, T. / Nezami, A. / Reynolds, J. / Alvi, K. / Goulet, L. / Stamos, D.
History
DepositionDec 13, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 9, 2014Provider: repository / Type: Initial release
Revision 1.1May 7, 2014Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software
Revision 1.3Feb 28, 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)26,5622
Polymers26,1831
Non-polymers3791
Water2,540141
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)69.040, 89.830, 97.960
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 / HSP 86 / HSP86 / Renal carcinoma antigen NY-REN-38


Mass: 26183.400 Da / Num. of mol.: 1 / Fragment: UNP residues 9-236
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P07900
#2: Chemical ChemComp-2R6 / 8-(2-methylpropyl)-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)-3,4-dihydroisoquinolin-1(2H)-one


Mass: 378.507 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H30N2O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 141 / 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: 57.59 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 20-25%PEGMME2K, 100mM cacodylate 6.5, 200mM magnesium chloride, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.8 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Aug 14, 2011
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8 Å / Relative weight: 1
ReflectionResolution: 1.96→66.21 Å / Num. all: 22213 / Num. obs: 21969 / % possible obs: 98.9 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Biso Wilson estimate: 32.73 Å2
Reflection shellResolution: 1.961→1.968 Å / % possible all: 99.6

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Processing

Software
NameVersionClassificationNB
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.1data extraction
PROCESSdata collection
PROCESSdata reduction
PROCESSdata scaling
BUSTER2.11.5refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.96→21.28 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.9266 / Occupancy max: 9 / Occupancy min: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2281 1123 5.12 %RANDOM
Rwork0.2015 ---
all0.2028 22225 --
obs0.2028 21948 98.75 %-
Displacement parametersBiso max: 92.68 Å2 / Biso mean: 34.6738 Å2 / Biso min: 0 Å2
Baniso -1Baniso -2Baniso -3
1--4.8867 Å20 Å20 Å2
2--0.3229 Å20 Å2
3---4.5638 Å2
Refine analyzeLuzzati coordinate error obs: 0.243 Å
Refinement stepCycle: LAST / Resolution: 1.96→21.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1644 0 28 141 1813
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d632SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes46HARMONIC2
X-RAY DIFFRACTIONt_gen_planes267HARMONIC5
X-RAY DIFFRACTIONt_it1736HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion237SEMIHARMONIC5
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_contact2110SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1736HARMONIC10.012
X-RAY DIFFRACTIONt_angle_deg2352HARMONIC11.39
X-RAY DIFFRACTIONt_omega_torsion2.07
X-RAY DIFFRACTIONt_other_torsion16.35
LS refinement shellResolution: 1.96→2.06 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2059 137 4.86 %
Rwork0.2139 2680 -
all0.2134 2817 -
obs--98.75 %

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