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- PDB-6u99: Hsp90a NTD covalently bound to sulfonyl fluoride probe 1 at K58 -

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Basic information

Entry
Database: PDB / ID: 6u99
TitleHsp90a NTD covalently bound to sulfonyl fluoride probe 1 at K58
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 / response to follicle-stimulating hormone / Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly / UTP binding / dATP binding ...sperm plasma membrane / sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / response to follicle-stimulating hormone / Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly / UTP binding / dATP binding / mitochondrial transport / negative regulation of striated muscle cell apoptotic process / HSP90-CDC37 chaperone complex / AP-3 adaptor complex binding / telomerase holoenzyme complex assembly / chaperone-mediated autophagy / 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 / positive regulation of cell size / dendritic growth cone / TPR domain binding / protein import into mitochondrial matrix / PIWI-interacting RNA (piRNA) biogenesis / response to dietary excess / response to caloric restriction / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / Sema3A PAK dependent Axon repulsion / response to salt stress / regulation of protein ubiquitination / response to unfolded protein / HSF1-dependent transactivation / cardiac muscle cell apoptotic process / regulation of protein-containing complex assembly / Attenuation phase / protein folding chaperone complex / HSF1 activation / enzyme-substrate adaptor activity / chaperone-mediated protein complex assembly / axonal growth cone / neurofibrillary tangle assembly / regulation of postsynaptic membrane neurotransmitter receptor levels / telomere maintenance via telomerase / positive regulation of lamellipodium assembly / RHOBTB2 GTPase cycle / Dengue virus activates/modulates innate and adaptive immune responses / nitric oxide metabolic process / response to isolation stress / protein unfolding / positive regulation of defense response to virus by host / Signaling by ERBB2 / skeletal muscle contraction / eNOS activation / positive regulation of telomere maintenance via telomerase / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / endocytic vesicle lumen / response to cold / 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 / cellular response to platelet-derived growth factor stimulus / lysosomal lumen / Recruitment of NuMA to mitotic centrosomes / ESR-mediated signaling / Anchoring of the basal body to the plasma membrane / activation of innate immune response / positive regulation of interferon-beta production / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / AURKA Activation by TPX2 / Constitutive Signaling by Overexpressed ERBB2 / protein tyrosine kinase binding / nitric-oxide synthase regulator activity / ATP-dependent protein folding chaperone / response to cocaine / VEGFR2 mediated vascular permeability / brush border membrane / cellular response to virus / positive regulation of protein import into nucleus / neuron migration / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / protein refolding / Regulation of actin dynamics for phagocytic cup formation / Signaling by ERBB2 KD Mutants / response to estrogen / VEGFA-VEGFR2 Pathway
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-Q2J / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 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 6, 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
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)29,3042
Polymers28,6801
Non-polymers6241
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 area10530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.700, 91.530, 98.850
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: 28679.990 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 BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P07900
#2: Chemical ChemComp-Q2J / 3-{[(3-{6-amino-8-[(6-iodo-2H-1,3-benzodioxol-5-yl)sulfanyl]-9H-purin-9-yl}propyl)amino]methyl}benzene-1-sulfinic acid


Mass: 624.474 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H21IN6O4S2 / 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
Has protein modificationY

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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: 3.24 Å3/Da / Density % sol: 62.07 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 20% PEG-3350, 0.2 M MgCl2, 0.1 M sodium acetate, pH 5.6

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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: Dec 2, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.11583 Å / Relative weight: 1
ReflectionResolution: 1.6→55.29 Å / Num. obs: 40255 / % possible obs: 99.74 % / Redundancy: 6.6 % / Biso Wilson estimate: 19.8 Å2 / Rmerge(I) obs: 0.03183 / Net I/σ(I): 42.72
Reflection shellResolution: 1.6→1.657 Å / Rmerge(I) obs: 0.1834 / Mean I/σ(I) obs: 9.78 / Num. unique obs: 3952

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Processing

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

2fwz


Resolution: 1.6→55.29 Å / SU ML: 0.1369 / Cross valid method: THROUGHOUT / σ(F): 1.39 / Phase error: 18.7803
RfactorNum. reflection% reflection
Rfree0.2038 1967 4.9 %
Rwork0.1777 --
obs0.179 40175 99.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 24.24 Å2
Refinement stepCycle: LAST / Resolution: 1.6→55.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1631 0 35 264 1930
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00591697
X-RAY DIFFRACTIONf_angle_d1.14092291
X-RAY DIFFRACTIONf_chiral_restr0.0553260
X-RAY DIFFRACTIONf_plane_restr0.0046288
X-RAY DIFFRACTIONf_dihedral_angle_d11.82081016
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.640.19811250.18362703X-RAY DIFFRACTION99.96
1.64-1.680.21391370.18212697X-RAY DIFFRACTION100
1.68-1.730.22591320.18512713X-RAY DIFFRACTION99.96
1.73-1.790.19281530.17942715X-RAY DIFFRACTION99.97
1.79-1.850.19231570.18052678X-RAY DIFFRACTION99.82
1.85-1.930.19581400.17972715X-RAY DIFFRACTION99.9
1.93-2.020.20641250.18322719X-RAY DIFFRACTION99.96
2.02-2.120.21731410.1822691X-RAY DIFFRACTION99.68
2.12-2.250.22051380.18112733X-RAY DIFFRACTION99.72
2.25-2.430.2111340.17922731X-RAY DIFFRACTION99.27
2.43-2.670.19081330.19112732X-RAY DIFFRACTION99.41
2.67-3.060.22521320.18692746X-RAY DIFFRACTION99.52
3.06-3.860.20371650.17382754X-RAY DIFFRACTION99.69
3.86-55.290.18811550.16422881X-RAY DIFFRACTION99.57

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