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- PDB-6lt8: HSP90 in complex with KW-2478 -

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Basic information

Entry
Database: PDB / ID: 6lt8
TitleHSP90 in complex with KW-2478
ComponentsHeat shock protein HSP 90-alphaHeat shock response
KeywordsCHAPERONE / HSP90 / KW-2478
Function / homology
Function and homology information


sperm mitochondrial sheath / dATP binding / Scavenging by Class F Receptors / sulfonylurea receptor binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / UTP binding / sperm plasma membrane / positive regulation of tau-protein kinase activity ...sperm mitochondrial sheath / dATP binding / Scavenging by Class F Receptors / sulfonylurea receptor binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / UTP binding / sperm plasma membrane / positive regulation of tau-protein kinase activity / protein insertion into mitochondrial outer membrane / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / Rho GDP-dissociation inhibitor binding / Uptake and function of diphtheria toxin / mitochondrial transport / 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 / PIWI-interacting RNA (piRNA) biogenesis / TPR domain binding / non-chaperonin molecular chaperone ATPase / regulation of postsynaptic membrane neurotransmitter receptor levels / dendritic growth cone / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / skeletal muscle contraction / positive regulation of cell size / HSF1-dependent transactivation / telomere maintenance via telomerase / response to unfolded protein / chaperone-mediated protein complex assembly / protein unfolding / HSF1 activation / regulation of protein-containing complex assembly / Attenuation phase / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / eNOS activation / axonal growth cone / DNA polymerase binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / positive regulation of cardiac muscle contraction / Recruitment of mitotic centrosome proteins and complexes / cardiac muscle cell apoptotic process / positive regulation of telomerase activity / Signaling by ERBB2 / positive regulation of defense response to virus by host / endocytic vesicle lumen / response to salt stress / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / activation of innate immune response / nitric-oxide synthase regulator activity / response to cold / positive regulation of interferon-beta production / lysosomal lumen / Constitutive Signaling by Overexpressed ERBB2 / AURKA Activation by TPX2 / ESR-mediated signaling / protein tyrosine kinase binding / VEGFR2 mediated vascular permeability / response to cocaine / brush border membrane / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / neuron migration / Constitutive Signaling by EGFRvIII / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 ECD mutants / tau protein binding / Signaling by ERBB2 KD Mutants / Regulation of necroptotic cell death / Regulation of actin dynamics for phagocytic cup formation / cellular response to virus / Downregulation of ERBB2 signaling / VEGFA-VEGFR2 Pathway / histone deacetylase binding / Aggrephagy / Chaperone Mediated Autophagy / positive regulation of protein import into nucleus / response to estrogen / positive regulation of protein catabolic process / The role of GTSE1 in G2/M progression after G2 checkpoint / regulation of protein localization / positive regulation of nitric oxide biosynthetic process / Regulation of PLK1 Activity at G2/M Transition / disordered domain specific binding / unfolded protein binding / melanosome
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-ET3 / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.593 Å
AuthorsCao, H.L.
CitationJournal: J.Struct.Biol. / Year: 2021
Title: Anti-NSCLC activity in vitro of Hsp90 N inhibitor KW-2478 and complex crystal structure determination of Hsp90 N -KW-2478.
Authors: Li, H.J. / Wang, Q.S. / Han, W. / Zhou, H. / Li, P. / Zhou, F. / Qin, W. / Zhao, D. / Zhou, X. / He, C.X. / Xing, L. / Li, P.Q. / Jin, X. / Yu, F. / He, J.H. / Cao, H.L.
History
DepositionJan 21, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 27, 2021Provider: repository / Type: Initial release
Revision 1.1Aug 11, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)28,9752
Polymers28,4011
Non-polymers5751
Water3,495194
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.686, 89.656, 98.432
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 response / 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: 28400.701 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-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P07900
#2: Chemical ChemComp-ET3 / 2-[2-ethyl-6-[3-methoxy-4-(2-morpholin-4-ylethoxy)phenyl]carbonyl-3,5-bis(oxidanyl)phenyl]-~{N},~{N}-bis(2-methoxyethyl)ethanamide


Mass: 574.662 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H42N2O9 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 194 / 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: 2.59 Å3/Da / Density % sol: 52.51 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 100 mM Tris-HCl (pH 8.5) 200 mM MgCl2 25% PEG4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.59→50 Å / Num. obs: 39761 / % possible obs: 99 % / Redundancy: 6.8 % / CC1/2: 0.998 / CC star: 1 / Net I/σ(I): 5.5
Reflection shellResolution: 1.59→1.62 Å / Num. unique obs: 3642 / CC1/2: 0.705

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
HKL-3000data scaling
PDB_EXTRACT3.25data extraction
HKL-3000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3TUH

3tuh


Resolution: 1.593→36.223 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 20.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1899 1999 5.07 %
Rwork0.171 37419 -
obs0.172 39418 99.03 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 105.3 Å2 / Biso mean: 38.4345 Å2 / Biso min: 22.74 Å2
Refinement stepCycle: final / Resolution: 1.593→36.223 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1664 0 41 194 1899
Biso mean--35.29 47.61 -
Num. residues----211
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0141733
X-RAY DIFFRACTIONf_angle_d1.3462334
X-RAY DIFFRACTIONf_chiral_restr0.11261
X-RAY DIFFRACTIONf_plane_restr0.007295
X-RAY DIFFRACTIONf_dihedral_angle_d9.6471040
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.593-1.63260.30461340.2773252295
1.6326-1.67680.26111420.2465262799
1.6768-1.72610.24371410.2146266499
1.7261-1.78180.22231400.2088261399
1.7818-1.84550.23941410.198265199
1.8455-1.91940.20441430.1751266999
1.9194-2.00670.19431430.1674267199
2.0067-2.11250.21431420.17172666100
2.1125-2.24480.19791430.1712268299
2.2448-2.41810.18911440.17472683100
2.4181-2.66140.19441460.17792723100
2.6614-3.04640.20741430.17682683100
3.0464-3.83740.18261470.16492748100
3.8374-36.2230.16671500.1572281798

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