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- PDB-6wbz: Structure of Human HDAC2 in complex with an ethyl ketone inhibito... -

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Basic information

Entry
Database: PDB / ID: 6wbz
TitleStructure of Human HDAC2 in complex with an ethyl ketone inhibitor containing a spiro-bicyclic group
ComponentsHistone deacetylase 2
KeywordsHYDROLASE/HYDROLASE Inhibitor / Histone Deacetylase / HYDROLASE / HYDROLASE-HYDROLASE Inhibitor complex
Function / homology
Function and homology information


protein de-2-hydroxyisobutyrylase activity / positive regulation of male mating behavior / negative regulation of peptidyl-lysine acetylation / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / negative regulation of dendritic spine development / histone decrotonylase activity / fungiform papilla formation / behavioral response to ethanol / negative regulation of MHC class II biosynthetic process ...protein de-2-hydroxyisobutyrylase activity / positive regulation of male mating behavior / negative regulation of peptidyl-lysine acetylation / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / negative regulation of dendritic spine development / histone decrotonylase activity / fungiform papilla formation / behavioral response to ethanol / negative regulation of MHC class II biosynthetic process / NuRD complex / positive regulation of interleukin-1 production / regulation of cell fate specification / negative regulation of stem cell population maintenance / EGR2 and SOX10-mediated initiation of Schwann cell myelination / negative regulation of transcription by competitive promoter binding / ESC/E(Z) complex / regulation of stem cell differentiation / STAT3 nuclear events downstream of ALK signaling / cellular response to dopamine / histone deacetylase / cardiac muscle hypertrophy / protein lysine deacetylase activity / positive regulation of signaling receptor activity / response to caffeine / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / histone deacetylase activity / embryonic digit morphogenesis / positive regulation of oligodendrocyte differentiation / positive regulation of stem cell population maintenance / Sin3-type complex / Notch-HLH transcription pathway / dendrite development / eyelid development in camera-type eye / odontogenesis of dentin-containing tooth / positive regulation of proteolysis / RNA Polymerase I Transcription Initiation / response to amyloid-beta / histone deacetylase complex / hair follicle placode formation / Regulation of MECP2 expression and activity / NF-kappaB binding / positive regulation of collagen biosynthetic process / response to hyperoxia / positive regulation of epithelial to mesenchymal transition / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / heterochromatin formation / MECP2 regulates neuronal receptors and channels / cellular response to retinoic acid / positive regulation of tyrosine phosphorylation of STAT protein / Regulation of TP53 Activity through Acetylation / cellular response to transforming growth factor beta stimulus / response to amphetamine / heat shock protein binding / SUMOylation of chromatin organization proteins / negative regulation of cell migration / response to cocaine / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / response to nicotine / Regulation of PTEN gene transcription / promoter-specific chromatin binding / HDACs deacetylate histones / negative regulation of transforming growth factor beta receptor signaling pathway / circadian regulation of gene expression / protein modification process / NoRC negatively regulates rRNA expression / negative regulation of DNA-binding transcription factor activity / NOTCH1 Intracellular Domain Regulates Transcription / cellular response to hydrogen peroxide / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / positive regulation of tumor necrosis factor production / negative regulation of neuron projection development / cellular response to heat / Factors involved in megakaryocyte development and platelet production / histone binding / RNA polymerase II-specific DNA-binding transcription factor binding / Potential therapeutics for SARS / response to lipopolysaccharide / chromosome, telomeric region / chromatin remodeling / response to xenobiotic stimulus / negative regulation of DNA-templated transcription / chromatin binding / positive regulation of cell population proliferation / chromatin / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / enzyme binding / positive regulation of transcription by RNA polymerase II / protein-containing complex / RNA binding / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
Histone deacetylase / Histone deacetylase domain / Arginase; Chain A / Histone deacetylase family / Histone deacetylase domain / Histone deacetylase domain superfamily / Histone deacetylase domain / Ureohydrolase domain superfamily / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
DI(HYDROXYETHYL)ETHER / Chem-TV7 / Histone deacetylase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.32 Å
AuthorsKlein, D.J. / Yu, W.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Discovery of ethyl ketone-based HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation.
Authors: Yu, W. / Liu, J. / Yu, Y. / Zhang, V. / Clausen, D. / Kelly, J. / Wolkenberg, S. / Beshore, D. / Duffy, J.L. / Chung, C.C. / Myers, R.W. / Klein, D.J. / Fells, J. / Holloway, K. / Wu, J. / ...Authors: Yu, W. / Liu, J. / Yu, Y. / Zhang, V. / Clausen, D. / Kelly, J. / Wolkenberg, S. / Beshore, D. / Duffy, J.L. / Chung, C.C. / Myers, R.W. / Klein, D.J. / Fells, J. / Holloway, K. / Wu, J. / Wu, G. / Howell, B.J. / Barnard, R.J.O. / Kozlowski, J.
History
DepositionMar 28, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 6, 2020Provider: repository / Type: Initial release
Revision 1.1Jun 3, 2020Group: Database references / Category: citation / citation_author / Item: _citation.journal_volume / _citation_author.name
Revision 1.2Mar 6, 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 / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone deacetylase 2
B: Histone deacetylase 2
C: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)133,01732
Polymers129,1863
Non-polymers3,83129
Water22,7711264
1
A: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,47412
Polymers43,0621
Non-polymers1,41211
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,1769
Polymers43,0621
Non-polymers1,1148
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,36811
Polymers43,0621
Non-polymers1,30610
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)92.390, 99.170, 139.600
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 3 molecules ABC

#1: Protein Histone deacetylase 2 / / HD2


Mass: 43061.988 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HDAC2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q92769, histone deacetylase

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Non-polymers , 6 types, 1293 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca
#5: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-TV7 / (1S)-N-{(1S)-7,7-dihydroxy-1-[5-(2-methoxyquinolin-3-yl)-1H-imidazol-2-yl]nonyl}-6-ethyl-6-azaspiro[2.5]octane-1-carboxamide


Mass: 563.731 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C32H45N5O4 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1264 / 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: 2.48 Å3/Da / Density % sol: 50.31 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 25% PEG 3350, 0.2 M ammonium sulfate, 0.1 M Hepes pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 22, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.32→48.56 Å / Num. obs: 298863 / % possible obs: 99.9 % / Redundancy: 6.6 % / CC1/2: 0.999 / Net I/σ(I): 13.1
Reflection shellResolution: 1.32→1.343 Å / Num. unique obs: 14601 / CC1/2: 0.62

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.32→19.26 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.962 / SU R Cruickshank DPI: 0.046 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.048 / SU Rfree Blow DPI: 0.049 / SU Rfree Cruickshank DPI: 0.047
RfactorNum. reflection% reflectionSelection details
Rfree0.192 15115 5.06 %RANDOM
Rwork0.172 ---
obs0.173 298743 99.9 %-
Displacement parametersBiso max: 189.31 Å2 / Biso mean: 24.48 Å2 / Biso min: 6.11 Å2
Baniso -1Baniso -2Baniso -3
1-2.5105 Å20 Å20 Å2
2---4.0515 Å20 Å2
3---1.541 Å2
Refine analyzeLuzzati coordinate error obs: 0.17 Å
Refinement stepCycle: final / Resolution: 1.32→19.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8859 0 231 1271 10361
Biso mean--38.97 38.24 -
Num. residues----1101
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3369SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1683HARMONIC8
X-RAY DIFFRACTIONt_it9507HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1131SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact12538SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9507HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12876HARMONIC21.05
X-RAY DIFFRACTIONt_omega_torsion3.37
X-RAY DIFFRACTIONt_other_torsion16.05
LS refinement shellResolution: 1.32→1.33 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2757 320 5.36 %
Rwork0.2602 5655 -
all0.261 5975 -
obs--96.83 %

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