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- PDB-6ceo: Structure of Hsp90 NTD with a GRP94-selective resorcinylic inhibitor. -

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Basic information

Entry
Database: PDB / ID: 6ceo
TitleStructure of Hsp90 NTD with a GRP94-selective resorcinylic inhibitor.
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE/INHIBITOR / Chaperone / Inhibitor / CHAPERONE-INHIBITOR complex
Function / homology
Function and homology information


sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / dATP binding / chaperone-mediated autophagy / sperm plasma membrane ...sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / dATP binding / chaperone-mediated autophagy / sperm plasma membrane / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / 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 / TPR domain binding / dendritic growth cone / 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 / protein folding chaperone complex / enzyme-substrate adaptor activity / response to unfolded protein / regulation of protein-containing complex assembly / HSF1 activation / Attenuation phase / chaperone-mediated protein complex assembly / neurofibrillary tangle assembly / RHOBTB2 GTPase cycle / regulation of postsynaptic membrane neurotransmitter receptor levels / telomere maintenance via telomerase / axonal growth cone / skeletal muscle contraction / positive regulation of lamellipodium assembly / nitric oxide metabolic process / positive regulation of defense response to virus by host / response to salt stress / positive regulation of telomere maintenance via telomerase / eNOS activation / DNA polymerase binding / Signaling by ERBB2 / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / 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 / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / lysosomal lumen / activation of innate immune response / ESR-mediated signaling / positive regulation of interferon-beta production / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / Constitutive Signaling by Overexpressed ERBB2 / response to cold / protein tyrosine kinase binding / 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 / Signaling by ERBB2 KD Mutants / DDX58/IFIH1-mediated induction of interferon-alpha/beta / cellular response to virus / positive regulation of protein import into nucleus / Regulation of actin dynamics for phagocytic cup formation / response to estrogen / Regulation of necroptotic cell death / VEGFA-VEGFR2 Pathway / tau protein binding / Downregulation of ERBB2 signaling / neuron migration / histone deacetylase binding / Chaperone Mediated Autophagy / extracellular matrix / positive regulation of nitric oxide biosynthetic process / disordered domain specific binding / Aggrephagy
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 90 / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase/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 90 / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase/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-D57 / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.896 Å
AuthorsQue, N.L.S. / Gewirth, D.T.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5P01CA186866 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)5R01CA095130 United States
CitationJournal: J. Med. Chem. / Year: 2018
Title: Structure Based Design of a Grp94-Selective Inhibitor: Exploiting a Key Residue in Grp94 To Optimize Paralog-Selective Binding.
Authors: Que, N.L.S. / Crowley, V.M. / Duerfeldt, A.S. / Zhao, J. / Kent, C.N. / Blagg, B.S.J. / Gewirth, D.T.
History
DepositionFeb 12, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 18, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 25, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Feb 20, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Mar 13, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_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)29,3919
Polymers28,7731
Non-polymers6188
Water2,864159
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area810 Å2
ΔGint-37 kcal/mol
Surface area10120 Å2
2
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)58,78318
Polymers57,5462
Non-polymers1,23716
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_765-x+2,-y+1,z1
Buried area3550 Å2
ΔGint-94 kcal/mol
Surface area18310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.440, 88.930, 99.933
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: 28773.145 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: N-Terminal Domain (residues 1-236) / Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta 2 (DE3) / References: UniProt: P07900
#2: Chemical ChemComp-D57 / dimethyl 2-[2-(1-benzyl-1H-imidazol-2-yl)ethyl]-4,6-dihydroxybenzene-1,3-dicarboxylate


Mass: 410.420 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22N2O6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 159 / 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: 2.53 Å3/Da / Density % sol: 51.32 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: PEG 2000 MME, MgCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.03334 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jul 13, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03334 Å / Relative weight: 1
ReflectionResolution: 1.896→50 Å / Num. obs: 23393 / % possible obs: 99.3 % / Redundancy: 3.08 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 26.5
Reflection shellResolution: 1.896→1.93 Å / Rmerge(I) obs: 0.422 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 1193 / % possible all: 99

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Processing

Software
NameVersionClassification
PHENIX(1.12rc0_2784: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.896→34.515 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.61
RfactorNum. reflection% reflection
Rfree0.2109 2000 8.61 %
Rwork0.1843 --
obs0.1866 23232 98.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.896→34.515 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1624 0 40 159 1823
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0071685
X-RAY DIFFRACTIONf_angle_d0.8442276
X-RAY DIFFRACTIONf_dihedral_angle_d7.2531012
X-RAY DIFFRACTIONf_chiral_restr0.053260
X-RAY DIFFRACTIONf_plane_restr0.004290
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8956-1.9430.29891280.25891370X-RAY DIFFRACTION90
1.943-1.99550.29611430.22121503X-RAY DIFFRACTION100
1.9955-2.05420.2361440.21061540X-RAY DIFFRACTION100
2.0542-2.12050.24941420.20851501X-RAY DIFFRACTION100
2.1205-2.19630.24991430.18751523X-RAY DIFFRACTION100
2.1963-2.28420.21131430.18891508X-RAY DIFFRACTION100
2.2842-2.38810.22111430.19181528X-RAY DIFFRACTION100
2.3881-2.5140.19551440.18891519X-RAY DIFFRACTION100
2.514-2.67150.2561440.20321532X-RAY DIFFRACTION100
2.6715-2.87760.24881430.19691529X-RAY DIFFRACTION100
2.8776-3.16710.21851440.19731525X-RAY DIFFRACTION100
3.1671-3.62490.19871450.17941542X-RAY DIFFRACTION99
3.6249-4.56530.16421460.15911550X-RAY DIFFRACTION98
4.5653-34.52070.19931480.16961562X-RAY DIFFRACTION95

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