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- PDB-7lt0: Hsp90a N-terminal inhibitor -

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Basic information

Entry
Database: PDB / ID: 7lt0
TitleHsp90a N-terminal inhibitor
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE / inhibitor / Hsp90
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 / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / AP-3 adaptor complex binding / Rho GDP-dissociation inhibitor binding / Respiratory syncytial virus genome replication / 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 / skeletal muscle contraction / Signaling by ERBB2 / eNOS activation / positive regulation of telomere maintenance via telomerase / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / response to cold / 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 / 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 / response to cocaine / ATP-dependent protein folding chaperone / 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. / 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 ...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-, 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
Similarity search - Domain/homology
Chem-ONJ / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.697 Å
AuthorsBalch, M. / Peng, S. / Deng, J. / Matts, R.
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2021
Title: Selective Inhibition of the Hsp90 alpha Isoform.
Authors: Mishra, S.J. / Khandelwal, A. / Banerjee, M. / Balch, M. / Peng, S. / Davis, R.E. / Merfeld, T. / Munthali, V. / Deng, J. / Matts, R.L. / Blagg, B.S.J.
History
DepositionFeb 18, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 3, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 10, 2021Group: 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 1.2Apr 7, 2021Group: Database references / Category: citation / citation_author / Item: _citation.title / _citation_author.name
Revision 1.3May 5, 2021Group: 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 1.4Oct 18, 2023Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms
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)33,8762
Polymers33,5001
Non-polymers3751
Water5,819323
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)66.614, 90.119, 97.967
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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 / Lipopolysaccharide-associated protein 2 / LAP-2 / LPS- ...Heat shock 86 kDa / HSP 86 / HSP86 / Lipopolysaccharide-associated protein 2 / LAP-2 / LPS-associated protein 2 / Renal carcinoma antigen NY-REN-38


Mass: 33500.238 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, non-chaperonin molecular chaperone ATPase
#2: Chemical ChemComp-ONJ / (1,3-dihydro-2H-isoindol-2-yl){3-[(3,4-dimethylphenyl)sulfanyl]-4-hydroxyphenyl}methanone


Mass: 375.483 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H21NO2S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 323 / 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: 2.19 Å3/Da / Density % sol: 43.95 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 23% PEGMME 2,000, 0.2 M magnesium chloride, 0.1M sodium cacodylate pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 14-ID-B / Wavelength: 1.19787 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jul 19, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.19787 Å / Relative weight: 1
ReflectionResolution: 1.697→50 Å / Num. obs: 32431 / % possible obs: 98.5 % / Redundancy: 12.1 % / Biso Wilson estimate: 21.14 Å2 / Rmerge(I) obs: 0.125 / Rpim(I) all: 0.037 / Rrim(I) all: 0.13 / Χ2: 4.474 / Net I/σ(I): 11
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.7-1.7312.50.99615550.8190.2891.0371.54597.2
1.73-1.7612.50.86415900.8820.2510.91.21297.5
1.76-1.7912.60.65315750.9110.1890.681.33697.4
1.79-1.8312.50.56215870.9290.1630.5861.41997.7
1.83-1.8712.50.46715980.9510.1360.4871.62797.9
1.87-1.9111.10.56815900.9370.1730.5943.52797.7
1.91-1.9611.80.59316100.870.1750.6199.76197.8
1.96-2.0212.60.2815970.9750.0810.2912.6398.5
2.02-2.0710.90.46315920.8550.1390.48410.5897.4
2.07-2.1411.70.28816010.970.0870.3014.85898.3
2.14-2.2212.60.17216140.990.050.1793.61199
2.22-2.3110.80.42616040.9160.1260.44414.33197.7
2.31-2.4112.60.14216150.9920.0410.1483.74899
2.41-2.5412.60.15316330.9910.0440.1594.86799.2
2.54-2.712.20.14216360.9920.0420.1485.86999.4
2.7-2.9112.50.09816550.9960.0290.1024.16399.5
2.91-3.212.50.0816500.9970.0230.0834.00599.7
3.2-3.6612.30.08116680.9980.0240.0855.86799.8
3.66-4.6112.20.06516940.9980.0190.0685.77499.8
4.61-5011.80.03117670.9990.0090.0321.25599.5

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.10.1_2155refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2CG9

2cg9


Resolution: 1.697→29.765 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 21.43 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.204 1993 6.18 %
Rwork0.1759 30270 -
obs0.1777 32263 97.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 72.88 Å2 / Biso mean: 27.6164 Å2 / Biso min: 12.58 Å2
Refinement stepCycle: final / Resolution: 1.697→29.765 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1635 0 27 323 1985
Biso mean--18.03 39.88 -
Num. residues----208
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061691
X-RAY DIFFRACTIONf_angle_d0.8252283
X-RAY DIFFRACTIONf_chiral_restr0.052258
X-RAY DIFFRACTIONf_plane_restr0.004290
X-RAY DIFFRACTIONf_dihedral_angle_d17.0191008
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.6972-1.73960.31611360.2716208497
1.7396-1.78670.22871390.2059209997
1.7867-1.83920.27971350.196214298
1.8392-1.89860.27491460.2212213998
1.8986-1.96640.34031410.3083205794
1.9664-2.04520.21311340.1722213498
2.0452-2.13820.24811420.2276211397
2.1382-2.25090.20571370.1871215198
2.2509-2.39190.24181490.1821215298
2.3919-2.57650.21331370.1715220599
2.5765-2.83550.18851480.1628217499
2.8355-3.24540.18541490.15842229100
3.2454-4.08720.16491470.14312241100
4.0872-29.7650.17551530.15912350100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.3-0.6374-0.69571.0330.86713.76830.0436-0.13560.01690.06730.1177-0.104-0.09460.2002-0.15210.17860.0022-0.00650.2261-0.01430.1907-20.2867-18.0627-18.0677
21.0824-0.27980.19051.7536-1.25052.4083-0.01470.0940.0967-0.07520.03510.1716-0.1844-0.1092-0.05710.15180.0098-0.01040.127-0.00380.1515-40.1357-6.4579-25.5451
31.07220.2538-0.7891.7619-0.76322.0831-0.07930.047-0.144-0.06110.0137-0.08160.0764-0.04650.06470.1736-0.0035-0.02260.1482-0.01640.1752-37.3067-18.349-23.5347
42.38460.2133-0.11952.25260.29864.38730.1153-0.15640.45260.1184-0.0585-0.2528-0.33390.7277-0.13890.2555-0.0332-0.00110.3588-0.05370.385-20.5735-6.1862-15.1262
51.3317-0.7384-0.07251.3044-0.27641.21820.06760.178-0.1534-0.17370.00030.11340.09310.1081-0.07560.1759-0.0027-0.01860.1633-0.01970.1864-32.0286-19.9722-26.7015
63.4987-0.9475-0.18643.61320.13432.5753-0.0639-0.3832-0.14130.2058-0.0414-0.03950.1228-0.07150.06960.1835-0.0153-0.00290.22810.04080.1416-39.5004-19.4886-6.7163
71.93820.7306-0.22644.8701-0.59911.46840.0679-0.2460.12850.4702-0.0781-0.028-0.2549-0.02680.02160.20080.01310.00310.239-0.00280.1785-46.3361-11.7369-15.3177
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 16 through 40 )A16 - 40
2X-RAY DIFFRACTION2chain 'A' and (resid 41 through 76 )A41 - 76
3X-RAY DIFFRACTION3chain 'A' and (resid 77 through 105 )A77 - 105
4X-RAY DIFFRACTION4chain 'A' and (resid 106 through 136 )A106 - 136
5X-RAY DIFFRACTION5chain 'A' and (resid 137 through 190 )A137 - 190
6X-RAY DIFFRACTION6chain 'A' and (resid 191 through 210 )A191 - 210
7X-RAY DIFFRACTION7chain 'A' and (resid 211 through 223 )A211 - 223

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