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- PDB-6u9a: Hsp90a NTD K58R bound reversibly to sulfonyl fluoride 5 -

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Basic information

Entry
Database: PDB / ID: 6u9a
TitleHsp90a NTD K58R bound reversibly to sulfonyl fluoride 5
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE/INHIBITOR / inhibitor / lysine-targeted inhibitor / CHAPERONE / CHAPERONE-INHIBITOR complex
Function / homology
Function and homology information


sperm plasma membrane / sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly / UTP binding / dATP binding / telomerase holoenzyme complex assembly ...sperm plasma membrane / sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly / UTP binding / dATP binding / telomerase holoenzyme complex assembly / chaperone-mediated autophagy / mitochondrial transport / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / 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 / Uptake and function of diphtheria toxin / dendritic growth cone / protein import into mitochondrial matrix / TPR domain binding / PIWI-interacting RNA (piRNA) biogenesis / non-chaperonin molecular chaperone ATPase / Assembly and release of respiratory syncytial virus (RSV) virions / positive regulation of cell size / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / protein folding chaperone complex / HSF1-dependent transactivation / response to unfolded protein / regulation of protein-containing complex assembly / protein unfolding / Attenuation phase / enzyme-substrate adaptor activity / HSF1 activation / chaperone-mediated protein complex assembly / neurofibrillary tangle assembly / axonal growth cone / telomere maintenance via telomerase / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / regulation of postsynaptic membrane neurotransmitter receptor levels / nitric oxide metabolic process / response to cold / positive regulation of defense response to virus by host / response to salt stress / skeletal muscle contraction / Signaling by ERBB2 / eNOS activation / cardiac muscle cell apoptotic process / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / positive regulation of telomere maintenance via telomerase / endocytic vesicle lumen / DNA polymerase binding / 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 / Recruitment of NuMA to mitotic centrosomes / lysosomal lumen / Anchoring of the basal body to the plasma membrane / ESR-mediated signaling / activation of innate immune response / positive regulation of interferon-beta production / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / protein tyrosine kinase binding / AURKA Activation by TPX2 / Constitutive Signaling by Overexpressed ERBB2 / nitric-oxide synthase regulator activity / ATP-dependent protein folding chaperone / VEGFR2 mediated vascular permeability / response to cocaine / brush border membrane / myelin sheath / Signaling by ERBB2 TMD/JMD mutants / neuron migration / cellular response to virus / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / positive regulation of protein import into nucleus / Signaling by ERBB2 KD Mutants / protein refolding / Regulation of actin dynamics for phagocytic cup formation / DDX58/IFIH1-mediated induction of interferon-alpha/beta / response to estrogen / VEGFA-VEGFR2 Pathway / Regulation of necroptotic cell death / tau protein binding / histone deacetylase binding / positive regulation of nitric oxide biosynthetic process / Downregulation of ERBB2 signaling / Chaperone Mediated Autophagy / disordered domain specific binding
Similarity search - Function
Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / 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-, 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 / Heat Shock Protein 90 / 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-, 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-Q2A / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsCuesta, A. / Wan, X. / Taunton, J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)F31CA214028 United States
CitationJournal: J.Am.Chem.Soc. / Year: 2020
Title: Ligand Conformational Bias Drives Enantioselective Modification of a Surface-Exposed Lysine on Hsp90.
Authors: Cuesta, A. / Wan, X. / Burlingame, A.L. / Taunton, J.
History
DepositionSep 7, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 19, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 4, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 11, 2023Group: 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)29,3912
Polymers28,7081
Non-polymers6831
Water4,756264
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area10460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.694, 92.742, 100.069
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Space group name HallI22
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z
#4: -x,-y,z
#5: x+1/2,y+1/2,z+1/2
#6: x+1/2,-y+1/2,-z+1/2
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2

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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: 28708.002 Da / Num. of mol.: 1 / Mutation: K58R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P07900
#2: Chemical ChemComp-Q2A / 3-{[(3S)-3-({6-amino-8-[(6-iodo-2H-1,3-benzodioxol-5-yl)sulfanyl]-9H-purin-9-yl}methyl)piperidin-1-yl]methyl}benzene-1-sulfonyl fluoride


Mass: 682.529 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H24FIN6O4S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 264 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.32 Å3/Da / Density % sol: 62.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 20% PEG-3350, 0.2 M MgCl2, 0.1 M sodium acetate, pH 5.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.11583 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Oct 5, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.11583 Å / Relative weight: 1
ReflectionResolution: 1.65→55.5 Å / Num. obs: 36931 / % possible obs: 96.02 % / Redundancy: 1.9 % / Biso Wilson estimate: 26.6 Å2 / Rmerge(I) obs: 0.03558 / Net I/σ(I): 8.36
Reflection shellResolution: 1.65→1.709 Å / Rmerge(I) obs: 0.5237 / Mean I/σ(I) obs: 1.09 / Num. unique obs: 3691 / % possible all: 99.41

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2FWZ

2fwz


Resolution: 1.65→55.5 Å / SU ML: 0.1795 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 27.9679 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflection
Rfree0.228 1968 5.44 %
Rwork0.1875 34212 -
obs0.1898 36180 96.02 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 37.96 Å2
Refinement stepCycle: LAST / Resolution: 1.65→55.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1626 0 39 264 1929
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00941774
X-RAY DIFFRACTIONf_angle_d1.27672410
X-RAY DIFFRACTIONf_chiral_restr0.0593269
X-RAY DIFFRACTIONf_plane_restr0.0062309
X-RAY DIFFRACTIONf_dihedral_angle_d11.98531070
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.65-1.690.39011350.29882488X-RAY DIFFRACTION99.36
1.69-1.740.31061470.27712489X-RAY DIFFRACTION99.51
1.74-1.790.26661420.25922505X-RAY DIFFRACTION99.36
1.79-1.850.29231420.26882533X-RAY DIFFRACTION99.7
1.85-1.910.35491270.31212264X-RAY DIFFRACTION90.4
1.91-1.990.46941360.37192203X-RAY DIFFRACTION87.73
1.99-2.080.25671360.21252540X-RAY DIFFRACTION99.7
2.08-2.190.21831580.19172468X-RAY DIFFRACTION98.94
2.19-2.330.31781270.25522316X-RAY DIFFRACTION90.65
2.33-2.510.22581390.17942502X-RAY DIFFRACTION98.25
2.51-2.760.23321450.17922462X-RAY DIFFRACTION96.84
2.76-3.160.20541450.16542463X-RAY DIFFRACTION95.57
3.16-3.980.21281460.1522453X-RAY DIFFRACTION94.92
3.98-55.50.15861430.1472526X-RAY DIFFRACTION93.62

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