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- PDB-8oxu: Crystal Structure of the Hsp90-LA1011 Complex -

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Basic information

Entry
Database: PDB / ID: 8oxu
TitleCrystal Structure of the Hsp90-LA1011 Complex
ComponentsATP-dependent molecular chaperone HSP82
KeywordsCHAPERONE / Inhibitor Complex
Function / homology
Function and homology information


The NLRP3 inflammasome / ESR-mediated signaling / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / eNOS activation / Extra-nuclear estrogen signaling / VEGFR2 mediated vascular permeability / HSF1-dependent transactivation / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / HSF1 activation / response to oxygen levels ...The NLRP3 inflammasome / ESR-mediated signaling / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / eNOS activation / Extra-nuclear estrogen signaling / VEGFR2 mediated vascular permeability / HSF1-dependent transactivation / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / HSF1 activation / response to oxygen levels / : / protein targeting to mitochondrion / box C/D snoRNP assembly / regulation of telomere maintenance / response to osmotic stress / 'de novo' protein folding / protein maturation / proteasome assembly / Neutrophil degranulation / positive regulation of telomere maintenance via telomerase / ATP-dependent protein folding chaperone / unfolded protein binding / protein folding / cellular response to heat / protein refolding / protein stabilization / perinuclear region of cytoplasm / ATP hydrolysis activity / protein-containing complex / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
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-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-W5R / ATP-dependent molecular chaperone HSP82
Similarity search - Component
Biological speciesSaccharomyces cerevisiae (brewer's yeast)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.94 Å
AuthorsRoe, S.M. / Prodromou, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
Citation
Journal: Biomolecules / Year: 2023
Title: The Crystal Structure of the Hsp90-LA1011 Complex and the Mechanism by Which LA1011 May Improve the Prognosis of Alzheimer's Disease.
Authors: Roe, S.M. / Torok, Z. / McGown, A. / Horvath, I. / Spencer, J. / Pazmany, T. / Vigh, L. / Prodromou, C.
#1: Journal: Acta Crystallogr.,Sect.D / Year: 2012
Title: Towards automated crystallographic structure refinement with phenix.refine.
Authors: Afonine, P.V. / Grosse-Kunstleve, R.W. / Echols, N. / Headd, J.J. / Moriarty, N.W. / Mustyakimov, M. / Terwilliger, T.C. / Urzhumtsev, A. / Zwart, P.H. / Adams, P.D.
#2: Journal: Acta Crystallogr D Struct Biol / Year: 2019
Title: Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix.
Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty ...Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty / Robert D Oeffner / Billy K Poon / Michael G Prisant / Randy J Read / Jane S Richardson / David C Richardson / Massimo D Sammito / Oleg V Sobolev / Duncan H Stockwell / Thomas C Terwilliger / Alexandre G Urzhumtsev / Lizbeth L Videau / Christopher J Williams / Paul D Adams /
Abstract: Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological ...Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.
History
DepositionMay 2, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 12, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 9, 2023Group: Data collection / Database references / Category: citation / citation_author / diffrn_source
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _diffrn_source.pdbx_synchrotron_site

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: ATP-dependent molecular chaperone HSP82
B: ATP-dependent molecular chaperone HSP82
C: ATP-dependent molecular chaperone HSP82
D: ATP-dependent molecular chaperone HSP82
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,2515
Polymers109,7534
Non-polymers4981
Water181
1
A: ATP-dependent molecular chaperone HSP82
B: ATP-dependent molecular chaperone HSP82


Theoretical massNumber of molelcules
Total (without water)54,8772
Polymers54,8772
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: ATP-dependent molecular chaperone HSP82
D: ATP-dependent molecular chaperone HSP82
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,3743
Polymers54,8772
Non-polymers4981
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)97.714, 97.714, 275.575
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and ((resid 439 through 444 and (name N...
d_2ens_1(chain "B" and ((resid 439 through 444 and (name N...
d_3ens_1(chain "C" and (resid 439 through 451 or (resid 452...
d_4ens_1(chain "D" and ((resid 439 through 444 and (name N...

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1LEUASNA1 - 231
d_21ens_1LEUGLNB1 - 158
d_22ens_1SERASNB161 - 233
d_31ens_1LEUGLNC1 - 158
d_32ens_1SERASNC160 - 232
d_41ens_1LEUGLNE1 - 158
d_42ens_1SERASNE161 - 233

NCS oper:
IDCodeMatrixVector
1given(-0.999452830884, 0.0273315868821, 0.0186285586141), (0.0328728718915, 0.883150791255, 0.467935950959), (-0.00366239418107, 0.468292285079, -0.883566026171)-82.8627644019, 21.4123068905, -75.473748212
2given(0.777571717108, 0.100461891354, -0.620717031455), (0.0954879643316, -0.994571302794, -0.0413518116562), (-0.621501627851, -0.0271170065646, -0.782943417198)-32.1352894033, 57.6383704858, -84.7297039896
3given(-0.798008336882, -0.097444106555, 0.594716184717), (-0.230924450244, -0.862074101349, -0.451112116954), (0.556647637691, -0.497325738205, 0.66544009315)-51.2213677457, 26.6312941768, 25.3634757527

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Components

#1: Protein
ATP-dependent molecular chaperone HSP82 / 82 kDa heat shock protein / Heat shock protein Hsp90 heat-inducible isoform


Mass: 27438.328 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: HSP82, HSP90, YPL240C / Production host: Escherichia coli (E. coli) / References: UniProt: P02829
#2: Chemical ChemComp-W5R / dimethyl 2,6-bis[2-(dimethylamino)ethyl]-1-methyl-4-[4-(trifluoromethyl)phenyl]-4~{H}-pyridine-3,5-dicarboxylate


Mass: 497.550 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H34F3N3O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1 / 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 Å3/Da / Density % sol: 58.96 %
Crystal growTemperature: 287 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: MES pH 7.5, Magnesium chloride hexahydrate, PEG Smear Medium, 2propanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.96864 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 20, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96864 Å / Relative weight: 1
ReflectionResolution: 2.94→92.1 Å / Num. obs: 23054 / % possible obs: 91.9 % / Redundancy: 9.2 % / Biso Wilson estimate: 70.11 Å2 / CC1/2: 0.995 / Net I/σ(I): 9
Reflection shellResolution: 2.94→3.19 Å / Redundancy: 4 % / Mean I/σ(I) obs: 1.4 / Num. unique obs: 1153 / CC1/2: 0.361 / % possible all: 58.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
PHENIX1.19_4092refinement
autoPROCdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.94→79.71 Å / SU ML: 0.3797 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 33.3056
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.3062 1125 4.88 %
Rwork0.247 21908 -
obs0.2498 23033 78.12 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 56.71 Å2
Refinement stepCycle: LAST / Resolution: 2.94→79.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6781 0 35 1 6817
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00546924
X-RAY DIFFRACTIONf_angle_d1.05099439
X-RAY DIFFRACTIONf_chiral_restr0.05071162
X-RAY DIFFRACTIONf_plane_restr0.00571211
X-RAY DIFFRACTIONf_dihedral_angle_d6.51631007
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AX-RAY DIFFRACTIONTorsion NCS1.07060574042
ens_1d_3AX-RAY DIFFRACTIONTorsion NCS1.25991057205
ens_1d_4AX-RAY DIFFRACTIONTorsion NCS1.22801006387
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.94-3.070.3299150.386336X-RAY DIFFRACTION9.79
3.07-3.230.4152640.34831179X-RAY DIFFRACTION34.58
3.23-3.430.35291440.32783080X-RAY DIFFRACTION89.13
3.43-3.70.34252070.27283378X-RAY DIFFRACTION98.46
3.7-4.070.30791680.24723446X-RAY DIFFRACTION98.31
4.07-4.660.27641790.22233409X-RAY DIFFRACTION97.77
4.66-5.870.31911640.24073466X-RAY DIFFRACTION97.37
5.87-79.710.27711840.22133614X-RAY DIFFRACTION95.81

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