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- PDB-7kbg: Structure of Human HDAC2 in complex with a 2-substituted benzamid... -

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Basic information

Entry
Database: PDB / ID: 7kbg
TitleStructure of Human HDAC2 in complex with a 2-substituted benzamide inhibitor (compound 20)
ComponentsHistone deacetylase 2
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HISTONE DEACETYLASE / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


positive regulation of male mating behavior / protein de-2-hydroxyisobutyrylase activity / 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 ...positive regulation of male mating behavior / protein de-2-hydroxyisobutyrylase activity / 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 / positive regulation of interleukin-1 production / NuRD complex / regulation of cell fate specification / negative regulation of transcription by competitive promoter binding / EGR2 and SOX10-mediated initiation of Schwann cell myelination / negative regulation of stem cell population maintenance / ESC/E(Z) complex / regulation of stem cell differentiation / cellular response to dopamine / STAT3 nuclear events downstream of ALK signaling / 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 / embryonic digit morphogenesis / histone deacetylase activity / positive regulation of oligodendrocyte differentiation / positive regulation of stem cell population maintenance / Notch-HLH transcription pathway / eyelid development in camera-type eye / Sin3-type complex / dendrite development / odontogenesis of dentin-containing tooth / RNA Polymerase I Transcription Initiation / response to amyloid-beta / positive regulation of proteolysis / 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 / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / positive regulation of epithelial to mesenchymal transition / MECP2 regulates neuronal receptors and channels / positive regulation of tyrosine phosphorylation of STAT protein / cellular response to retinoic acid / cellular response to transforming growth factor beta stimulus / Regulation of TP53 Activity through Acetylation / heat shock protein binding / response to amphetamine / SUMOylation of chromatin organization proteins / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / negative regulation of cell migration / Regulation of endogenous retroelements by KRAB-ZFP proteins / Regulation of PTEN gene transcription / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / response to cocaine / HDACs deacetylate histones / promoter-specific chromatin binding / response to nicotine / negative regulation of transforming growth factor beta receptor signaling pathway / circadian regulation of gene expression / NoRC negatively regulates rRNA expression / negative regulation of DNA-binding transcription factor activity / protein modification process / heterochromatin formation / NOTCH1 Intracellular Domain Regulates Transcription / histone deacetylase binding / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / cellular response to hydrogen peroxide / positive regulation of tumor necrosis factor production / negative regulation of neuron projection development / Factors involved in megakaryocyte development and platelet production / cellular response to heat / 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 family / Histone deacetylase domain / Histone deacetylase domain superfamily / Histone deacetylase domain / Ureohydrolase domain superfamily
Similarity search - Domain/homology
DI(HYDROXYETHYL)ETHER / Chem-WBA / 2,5-dichloro-1H-benzimidazole / Histone deacetylase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.26 Å
AuthorsKlein, D.J. / Liu, J.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Discovery of Highly Selective and Potent HDAC3 Inhibitors Based on a 2-Substituted Benzamide Zinc Binding Group.
Authors: Liu, J. / Yu, Y. / Kelly, J. / Sha, D. / Alhassan, A.B. / Yu, W. / Maletic, M.M. / Duffy, J.L. / Klein, D.J. / Holloway, M.K. / Carroll, S. / Howell, B.J. / Barnard, R.J.O. / Wolkenberg, S. / Kozlowski, J.A.
History
DepositionOct 2, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 30, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)133,31835
Polymers129,1863
Non-polymers4,13232
Water20,2851126
1
A: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,45412
Polymers43,0621
Non-polymers1,39211
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,25210
Polymers43,0621
Non-polymers1,1909
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,61313
Polymers43,0621
Non-polymers1,55112
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)92.260, 99.270, 139.020
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 , 8 types, 1158 molecules

#2: Chemical ChemComp-ZN / ZINC ION


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


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-WBA / N-{(1S)-5-[(2-fluoro-6-hydroxybenzene-1-carbonyl)amino]-1-[5-(naphthalen-2-yl)-1H-imidazol-2-yl]pentyl}-1,3-thiazole-5-carboxamide


Mass: 543.612 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C29H26FN5O3S / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Chemical ChemComp-WBD / 2,5-dichloro-1H-benzimidazole


Mass: 187.026 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H4Cl2N2
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1126 / 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: 2.46 Å3/Da / Density % sol: 50.08 %
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: CLSI / Beamline: 08ID-1 / Wavelength: 0.9813 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Sep 16, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9813 Å / Relative weight: 1
ReflectionResolution: 1.26→50 Å / Num. obs: 335871 / % possible obs: 98.3 % / Redundancy: 6 % / Rmerge(I) obs: 0.065 / Net I/σ(I): 23.8
Reflection shellResolution: 1.26→1.31 Å / Rmerge(I) obs: 0.919 / Mean I/σ(I) obs: 2 / Num. unique obs: 32760

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (19-MAR-2020)refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
HKL-2000data scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.26→25.08 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.959 / SU R Cruickshank DPI: 0.044 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.046 / SU Rfree Blow DPI: 0.045 / SU Rfree Cruickshank DPI: 0.044
RfactorNum. reflection% reflectionSelection details
Rfree0.1964 17056 5.08 %RANDOM
Rwork0.1841 ---
obs0.1847 335664 98.2 %-
Displacement parametersBiso max: 156.53 Å2 / Biso mean: 20.04 Å2 / Biso min: 5.58 Å2
Baniso -1Baniso -2Baniso -3
1-2.4774 Å20 Å20 Å2
2---3.6379 Å20 Å2
3---1.1605 Å2
Refine analyzeLuzzati coordinate error obs: 0.16 Å
Refinement stepCycle: final / Resolution: 1.26→25.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8869 0 245 1126 10240
Biso mean--30.67 31.77 -
Num. residues----1102
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3325SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1739HARMONIC8
X-RAY DIFFRACTIONt_it9524HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1147SEMIHARMONIC5
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_contact9875SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9524HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg12889HARMONIC20.96
X-RAY DIFFRACTIONt_omega_torsion3.41
X-RAY DIFFRACTIONt_other_torsion15.35
LS refinement shellResolution: 1.26→1.27 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2153 367 5.47 %
Rwork0.2228 6347 -
all0.2224 6714 -
obs--89.08 %

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