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- PDB-5nyh: Crystal Structure of Hsp90-alpha N-Domain in complex with Indazol... -

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Basic information

Entry
Database: PDB / ID: 5nyh
TitleCrystal Structure of Hsp90-alpha N-Domain in complex 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 / 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-9EK / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.65 Å
AuthorsAmaral, M.
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
DepositionMay 11, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 18, 2018Provider: 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 1.3May 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)26,1632
Polymers25,7141
Non-polymers4501
Water3,783210
1
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)52,3274
Polymers51,4282
Non-polymers8992
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_565-x,-y+1,z1
Buried area1640 Å2
ΔGint-8 kcal/mol
Surface area19700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.979, 88.540, 97.091
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-9EK / ~{N}-methyl-~{N}-(4-morpholin-4-ylphenyl)-6-oxidanyl-3-pyrrolidin-1-ylcarbonyl-2~{H}-indazole-5-carboxamide


Mass: 449.502 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H27N5O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 210 / 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: 2.89 Å3/Da / Density % sol: 57.47 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop
Details: 0.2 M sodium fluoride, 0.1 M Bis Tris propane, pH 8.5, 20 % w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 18, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.65→48.54 Å / Num. obs: 36566 / % possible obs: 99.7 % / Redundancy: 6.27 % / Biso Wilson estimate: 34.23 Å2 / Rmerge(I) obs: 0.097 / Net I/σ(I): 11.25
Reflection shellResolution: 1.65→1.75 Å / Rmerge(I) obs: 1.205 / Mean I/σ(I) obs: 1.34 / % possible all: 98.5

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementResolution: 1.65→23.11 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.955 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.088 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.093 / SU Rfree Blow DPI: 0.089 / SU Rfree Cruickshank DPI: 0.085
RfactorNum. reflection% reflectionSelection details
Rfree0.226 1829 5 %RANDOM
Rwork0.207 ---
obs0.208 36566 99.8 %-
Displacement parametersBiso mean: 35.88 Å2
Baniso -1Baniso -2Baniso -3
1-2.8243 Å20 Å20 Å2
2---2.7451 Å20 Å2
3----0.0793 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: 1 / Resolution: 1.65→23.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1644 0 33 210 1887
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.011742HARMONIC2
X-RAY DIFFRACTIONt_angle_deg12356HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d639SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes48HARMONIC2
X-RAY DIFFRACTIONt_gen_planes275HARMONIC5
X-RAY DIFFRACTIONt_it1742HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.29
X-RAY DIFFRACTIONt_other_torsion14.97
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion235SEMIHARMONIC5
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_contact2267SEMIHARMONIC4
LS refinement shellResolution: 1.65→1.7 Å / Rfactor Rfree error: 0 / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.387 148 5.02 %
Rwork0.354 2798 -
all0.356 2946 -
obs--99.16 %

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