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- PDB-7p2u: Crystal structure of Schistosoma mansoni HDAC8 in complex with a ... -

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Basic information

Entry
Database: PDB / ID: 7p2u
TitleCrystal structure of Schistosoma mansoni HDAC8 in complex with a 3-chlorophenyl-spiroindoline capped hydroxamate-based inhibitor, bound to a novel site
ComponentsHistone deacetylase 8
KeywordsHYDROLASE / SmHDAC8 / novel binding-site / HDACi / histone-deacetilase inhibitor complex
Function / homology
Function and homology information


histone deacetylase / histone deacetylase activity / heterochromatin formation / metal ion binding / nucleus
Similarity search - Function
: / Histone deacetylase family / Histone deacetylase domain / Histone deacetylase domain superfamily / Histone deacetylase domain / Ureohydrolase domain superfamily
Similarity search - Domain/homology
Chem-4WB / : / L(+)-TARTARIC ACID / histone deacetylase
Similarity search - Component
Biological speciesSchistosoma mansoni (invertebrata)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsSaccoccia, F. / Gemma, S. / Campiani, G. / Ruberti, G.
CitationJournal: J.Biol.Chem. / Year: 2022
Title: Crystal structures of Schistosoma mansoni histone deacetylase 8 reveal a novel binding site for allosteric inhibitors.
Authors: Saccoccia, F. / Pozzetti, L. / Gimmelli, R. / Butini, S. / Guidi, A. / Papoff, G. / Giannaccari, M. / Brogi, S. / Scognamiglio, V. / Gemma, S. / Ruberti, G. / Campiani, G.
History
DepositionJul 6, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 20, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 31, 2022Group: 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.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Sep 28, 2022Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.3Jan 31, 2024Group: 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: Histone deacetylase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,6708
Polymers49,8341
Non-polymers8367
Water2,990166
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: Steady-state kinetics experiments confirmed that ligand behaved as an allosteric inhibitor; fluorescence spectra - at equilibrium - confirmed the binding at a novel binding site; all of the ...Evidence: Steady-state kinetics experiments confirmed that ligand behaved as an allosteric inhibitor; fluorescence spectra - at equilibrium - confirmed the binding at a novel binding site; all of the above experiments were confirmed by dedicated mutant form. More details will be released in related publication
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)70.369, 70.369, 186.346
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Histone deacetylase 8


Mass: 49834.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Schistosoma mansoni (invertebrata) / Gene: HDAC8 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: A5H660

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Non-polymers , 6 types, 173 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: K
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-TLA / L(+)-TARTARIC ACID


Mass: 150.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O6
#6: Chemical ChemComp-4WB / 5-[[(2R)-2-(3-chlorophenyl)-1'-methyl-spiro[2H-indole-3,4'-piperidine]-1-yl]methyl]-N-oxidanyl-thiophene-2-carboxamide


Mass: 468.011 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H26ClN3O2S / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 166 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.31 Å3/Da / Density % sol: 46.71 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / Details: 20-22% PEG 3350, 200mM sodium/potassium tartrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ELETTRA / Beamline: 11.2C / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 4, 2020
RadiationMonochromator: Double Crystal Si111 with LN2 closed loop cooling
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→46.63 Å / Num. obs: 44460 / % possible obs: 100 % / Redundancy: 12.6 % / CC1/2: 0.999 / Rmerge(I) obs: 0.091 / Rpim(I) all: 0.027 / Rrim(I) all: 0.095 / Net I/σ(I): 15
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.8-1.8411.93.5343056325720.4981.063.6930.899.3
9-46.599.50.0342724510.9990.0110.03256.599.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4bz5

4bz5


Resolution: 1.8→46.63 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.959 / SU B: 3.651 / SU ML: 0.103 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.116 / ESU R Free: 0.113 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY. Used automatic weighting to optimize X-ray to stereochemistry weight
RfactorNum. reflection% reflectionSelection details
Rfree0.2132 2204 5 %RANDOM
Rwork0.179 ---
obs0.1808 42160 99.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 149.34 Å2 / Biso mean: 40.964 Å2 / Biso min: 25.16 Å2
Baniso -1Baniso -2Baniso -3
1-1.35 Å2-0 Å2-0 Å2
2--1.35 Å2-0 Å2
3----2.7 Å2
Refinement stepCycle: final / Resolution: 1.8→46.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3276 0 47 166 3489
Biso mean--54.57 45.74 -
Num. residues----409
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0133457
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173161
X-RAY DIFFRACTIONr_angle_refined_deg1.561.6374711
X-RAY DIFFRACTIONr_angle_other_deg1.3581.5757282
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9345415
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.19621.73185
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.83615543
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.491521
X-RAY DIFFRACTIONr_chiral_restr0.0840.2433
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.023912
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02834
LS refinement shellResolution: 1.8→1.847 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.331 155 -
Rwork0.341 3066 -
all-3221 -
obs--99.85 %

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