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- PDB-7zzr: HDAC2 in complex with inhibitory ligand -

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Basic information

Entry
Database: PDB / ID: 7zzr
TitleHDAC2 in complex with inhibitory ligand
ComponentsHistone deacetylase 2
KeywordsTRANSCRIPTION / chromatin binding / transcription regulation / protein de-acetylation
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 / 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 / fungiform papilla formation / behavioral response to ethanol / positive regulation of interleukin-1 production / negative regulation of MHC class II biosynthetic process / NuRD complex / regulation of cell fate specification / EGR2 and SOX10-mediated initiation of Schwann cell myelination / negative regulation of transcription by competitive promoter binding / 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 / Sin3-type complex / eyelid development in camera-type eye / 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 / positive regulation of epithelial to mesenchymal transition / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / MECP2 regulates neuronal receptors and channels / cellular response to retinoic acid / 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 / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / negative regulation of cell migration / 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 / 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 / histone binding / cellular response to heat / RNA polymerase II-specific DNA-binding transcription factor binding / Potential therapeutics for SARS / response to lipopolysaccharide / chromosome, telomeric region / response to xenobiotic stimulus / chromatin remodeling / 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
Chem-KJN / DI(HYDROXYETHYL)ETHER / Histone deacetylase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.168 Å
AuthorsCleasby, A. / Tisi, D.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Other private United Kingdom
CitationJournal: Acs Med.Chem.Lett. / Year: 2022
Title: Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor.
Authors: Tamanini, E. / Miyamura, S. / Buck, I.M. / Cons, B.D. / Dawson, L. / East, C. / Futamura, T. / Goto, S. / Griffiths-Jones, C. / Hashimoto, T. / Heightman, T.D. / Ishikawa, S. / Ito, H. / ...Authors: Tamanini, E. / Miyamura, S. / Buck, I.M. / Cons, B.D. / Dawson, L. / East, C. / Futamura, T. / Goto, S. / Griffiths-Jones, C. / Hashimoto, T. / Heightman, T.D. / Ishikawa, S. / Ito, H. / Kaneko, Y. / Kawato, T. / Kondo, K. / Kurihara, N. / McCarthy, J.M. / Mori, Y. / Nagase, T. / Nakaishi, Y. / Reeks, J. / Sato, A. / Schopf, P. / Tai, K. / Tamai, T. / Tisi, D. / Woolford, A.J.
History
DepositionMay 26, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 21, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 2, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)172,24132
Polymers169,6813
Non-polymers2,56029
Water16,358908
1
A: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1449
Polymers56,5601
Non-polymers5848
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,90814
Polymers56,5601
Non-polymers1,34813
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1889
Polymers56,5601
Non-polymers6288
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)91.991, 97.700, 138.849
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 / Protein deacylase HDAC2


Mass: 56560.285 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, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides

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Non-polymers , 9 types, 937 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.: 3 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Na
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-KJN / [(2~{R})-1-(dimethylamino)-1-oxidanylidene-4-phenyl-butan-2-yl]azanium


Mass: 207.292 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C12H19N2O / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-NHE / 2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID / N-CYCLOHEXYLTAURINE / CHES


Mass: 207.290 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H17NO3S / Comment: pH buffer*YM
#8: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#9: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C4H10O3
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 908 / 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

Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 41% PEG 300 0.1M pH=8.8 CHES/NaOH

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54178 Å
DetectorType: DECTRIS EIGER X 1M / Detector: PIXEL / Date: Feb 8, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.168→79.9 Å / Num. obs: 62291 / % possible obs: 90.9 % / Redundancy: 3 % / Rrim(I) all: 0.357 / Net I/σ(I): 2.7
Reflection shellResolution: 2.17→2.24 Å / Num. unique obs: 6061 / Rrim(I) all: 1.41

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (20-APR-2021)refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.168→76.69 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.887 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.338 / SU Rfree Blow DPI: 0.231
Details: HYDROGENS WERE FULLY REFINED U VALUES : WITH TLS ADDED WITH FULL OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT ...Details: HYDROGENS WERE FULLY REFINED U VALUES : WITH TLS ADDED WITH FULL OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2467 2923 4.84 %RANDOM
Rwork0.1884 ---
obs0.1912 60334 90 %-
Displacement parametersBiso max: 75.87 Å2 / Biso mean: 24.331 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1-1.5899 Å20 Å20 Å2
2---4.3198 Å20 Å2
3---2.73 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å
Refinement stepCycle: final / Resolution: 2.168→76.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8879 0 212 908 9999
Biso mean--27.46 32.56 -
Num. residues----1102
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3936SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes2945HARMONIC16
X-RAY DIFFRACTIONt_it18026HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1123SEMIHARMONIC5
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_contact15279SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d18026HARMONIC20.012
X-RAY DIFFRACTIONt_angle_deg32355HARMONIC21.04
X-RAY DIFFRACTIONt_omega_torsion6.62
X-RAY DIFFRACTIONt_other_torsion16.31
LS refinement shellResolution: 2.17→2.18 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3389 61 5.05 %
Rwork0.2676 1146 -
all0.2714 1207 -
obs--91.51 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.1855-0.0861-0.23570.09680.03890.585-0.008-0.03820.0008-0.0499-0.0277-0.01310.010.01050.0357-0.0229-0.01530.0252-0.0149-0.01110.001612.4953-22.9408-1.6466
20.2958-0.2149-0.01250.1531-0.05820.35250.0041-0.0294-0.0186-0.01680.0035-0.015-0.01120.0136-0.0075-0.0225-0.0184-0.0048-0.02830.01740.01871.0444-38.329836.5883
30.5546-0.0683-0.26480.39570.32660.33110.0316-0.02650.06160.0693-0.07190.06010.0725-0.00120.0403-0.0568-0.03140.025-0.0013-0.02480.009649.3541-23.731347.5606
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|11 - A|603 }A11 - 603
2X-RAY DIFFRACTION2{ B|14 - B|604 }B14 - 604
3X-RAY DIFFRACTION3{ C|13 - C|603 }C13 - 603

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