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- PDB-7ltk: STRUCTURE OF HUMAN HDAC2 IN COMPLEX WITH AN INHIBITOR THAT LACKS ... -

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Basic information

Entry
Database: PDB / ID: 7ltk
TitleSTRUCTURE OF HUMAN HDAC2 IN COMPLEX WITH AN INHIBITOR THAT LACKS A ZINC BINDING GROUP (COMPOUND 12)
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 / behavioral response to ethanol / fungiform papilla formation / positive regulation of interleukin-1 production ...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 / behavioral response to ethanol / fungiform papilla formation / positive regulation of interleukin-1 production / negative regulation of MHC class II biosynthetic process / 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 / regulation of stem cell differentiation / NuRD complex / ESC/E(Z) complex / 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 / positive regulation of oligodendrocyte differentiation / histone deacetylase activity / Sin3-type complex / positive regulation of stem cell population maintenance / Notch-HLH transcription pathway / dendrite development / eyelid development in camera-type eye / 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 / heterochromatin formation / positive regulation of epithelial to mesenchymal transition / cellular response to retinoic acid / MECP2 regulates neuronal receptors and channels / positive regulation of tyrosine phosphorylation of STAT protein / 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 / negative regulation of cell migration / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / response to cocaine / Regulation of PTEN gene transcription / HDACs deacetylate histones / promoter-specific chromatin binding / negative regulation of transforming growth factor beta receptor signaling pathway / circadian regulation of gene expression / response to nicotine / protein modification process / NoRC negatively regulates rRNA expression / negative regulation of DNA-binding transcription factor activity / NOTCH1 Intracellular Domain Regulates Transcription / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / cellular response to hydrogen peroxide / 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 / enzyme binding / negative regulation of transcription by RNA polymerase II / 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
ACETATE ION / DI(HYDROXYETHYL)ETHER / Chem-YEM / Histone deacetylase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.59 Å
AuthorsKlein, D.J. / Beshore, D.C.
CitationJournal: Acs Med.Chem.Lett. / Year: 2021
Title: Redefining the Histone Deacetylase Inhibitor Pharmacophore: High Potency with No Zinc Cofactor Interaction.
Authors: Beshore, D.C. / Adam, G.C. / Barnard, R.J.O. / Burlein, C. / Gallicchio, S.N. / Holloway, M.K. / Krosky, D. / Lemaire, W. / Myers, R.W. / Patel, S. / Plotkin, M.A. / Powell, D.A. / Rada, V. ...Authors: Beshore, D.C. / Adam, G.C. / Barnard, R.J.O. / Burlein, C. / Gallicchio, S.N. / Holloway, M.K. / Krosky, D. / Lemaire, W. / Myers, R.W. / Patel, S. / Plotkin, M.A. / Powell, D.A. / Rada, V. / Cox, C.D. / Coleman, P.J. / Klein, D.J. / Wolkenberg, S.E.
History
DepositionFeb 19, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 5, 2021Provider: 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)131,65924
Polymers129,1863
Non-polymers2,47321
Water18,5911032
1
A: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,9929
Polymers43,0621
Non-polymers9308
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,8868
Polymers43,0621
Non-polymers8247
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,7807
Polymers43,0621
Non-polymers7186
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)92.160, 98.430, 139.200
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, 1053 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-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#5: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-YEM / N-{(1S)-1-[5-(2-methoxyquinolin-3-yl)-1H-imidazol-2-yl]pentyl}-1-methylazetidine-3-carboxamide


Mass: 407.509 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C23H29N5O2 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1032 / 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: 2.44 Å3/Da / Density % sol: 49.66 %
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: Aug 9, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.59→48.372 Å / Num. obs: 169724 / % possible obs: 99.9 % / Redundancy: 6.7 % / CC1/2: 0.999 / Net I/σ(I): 12.6
Reflection shellResolution: 1.59→1.617 Å / Num. unique obs: 8271 / CC1/2: 0.564

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.59→23.2 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.955 / SU R Cruickshank DPI: 0.076 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.08 / SU Rfree Blow DPI: 0.079 / SU Rfree Cruickshank DPI: 0.077
RfactorNum. reflection% reflectionSelection details
Rfree0.198 8405 4.95 %RANDOM
Rwork0.172 ---
obs0.173 169640 99.9 %-
Displacement parametersBiso max: 179.35 Å2 / Biso mean: 32.38 Å2 / Biso min: 11.26 Å2
Baniso -1Baniso -2Baniso -3
1-2.4471 Å20 Å20 Å2
2---6.4603 Å20 Å2
3---4.0131 Å2
Refine analyzeLuzzati coordinate error obs: 0.2 Å
Refinement stepCycle: final / Resolution: 1.59→23.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8850 0 153 1039 10042
Biso mean--42.36 46.28 -
Num. residues----1098
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3288SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1655HARMONIC8
X-RAY DIFFRACTIONt_it9359HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1115SEMIHARMONIC5
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_contact12067SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9359HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12635HARMONIC21
X-RAY DIFFRACTIONt_omega_torsion2.82
X-RAY DIFFRACTIONt_other_torsion16.34
LS refinement shellResolution: 1.59→1.6 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.3203 191 5.63 %
Rwork0.2773 3202 -
all0.2797 3393 -
obs--97.73 %

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