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- PDB-7zzu: Inhibitory Ligand binding to HDAC2 -

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Basic information

Entry
Database: PDB / ID: 7zzu
TitleInhibitory Ligand binding to HDAC2
ComponentsHistone deacetylase 2
KeywordsTRANSCRIPTION / protein deacetylation / transcriptional repressor complex / chromatin binding
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 / odontogenesis of dentin-containing tooth / eyelid development in camera-type eye / Sin3-type complex / dendrite development / 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 / 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 / cellular response to retinoic acid / positive regulation of tyrosine phosphorylation of STAT protein / cellular response to transforming growth factor beta stimulus / heat shock protein binding / Regulation of TP53 Activity through Acetylation / 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 / Regulation of endogenous retroelements by KRAB-ZFP proteins / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / response to nicotine / HDACs deacetylate histones / promoter-specific chromatin binding / 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 / 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 / response to lipopolysaccharide / Potential therapeutics for SARS / 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
Chem-KKI / DI(HYDROXYETHYL)ETHER / Histone deacetylase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.85 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)172,94233
Polymers169,6813
Non-polymers3,26130
Water7,440413
1
A: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,08015
Polymers56,5601
Non-polymers1,52014
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,64311
Polymers56,5601
Non-polymers1,08310
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,2187
Polymers56,5601
Non-polymers6586
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)92.350, 98.352, 139.291
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, 443 molecules

#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#4: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical ChemComp-ZN / ZINC ION


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


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#7: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Na
#8: Chemical ChemComp-KKI / 2-[4-[(2~{R},4~{S})-4-phenylpyrrolidin-2-yl]carbonylpiperazin-1-yl]pyridine-3-carbonitrile


Mass: 361.440 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C21H23N5O / Feature type: SUBJECT OF INVESTIGATION
#9: 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 / Feature type: SUBJECT OF INVESTIGATION / Comment: pH buffer*YM
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 413 / 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: 43% 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: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 30, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. obs: 108658 / % possible obs: 98.9 % / Redundancy: 4.7 % / Rrim(I) all: 0.069 / Net I/σ(I): 21
Reflection shellResolution: 1.85→1.86 Å / Num. unique obs: 11470 / Rrim(I) all: 0.428

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Processing

Software
NameVersionClassification
REFMAC5.8.0232refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.85→48.45 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.946 / SU B: 4.271 / SU ML: 0.067 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.113 / ESU R Free: 0.106 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1818 5334 5 %RANDOM
Rwork0.1537 ---
obs0.1551 101782 98.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 92.91 Å2 / Biso mean: 25.873 Å2 / Biso min: 7.58 Å2
Baniso -1Baniso -2Baniso -3
1-0.07 Å2-0 Å2-0 Å2
2---0.37 Å20 Å2
3---0.3 Å2
Refinement stepCycle: final / Resolution: 1.85→48.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8883 0 357 413 9653
Biso mean--37.67 30.32 -
Num. residues----1103
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0159436
X-RAY DIFFRACTIONr_bond_other_d0.0010.0178260
X-RAY DIFFRACTIONr_angle_refined_deg1.3861.75712712
X-RAY DIFFRACTIONr_angle_other_deg0.5031.75119396
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.4085.3111159
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.58420.92452
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.74215.1351517
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.5971554
X-RAY DIFFRACTIONr_chiral_restr0.0720.21137
X-RAY DIFFRACTIONr_gen_planes_refined0.0010.02110561
X-RAY DIFFRACTIONr_gen_planes_other00.021835
LS refinement shellResolution: 1.85→1.898 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.232 357 -
Rwork0.2 6477 -
all-6834 -
obs--85.94 %
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)
11.8162-0.65350.12821.0222-0.26691.4049-0.0094-0.02150.0103-0.0014-0.0371-0.05670.00070.07050.04650.016-0.0165-0.00550.02340.01040.00651.1282-38.512136.651
20.9374-0.3115-0.43421.3692-0.00151.4768-0.0443-0.0723-0.0356-0.0448-0.0164-0.0070.03140.03770.06070.0274-0.02010.01880.0474-0.01190.015212.4035-23.0048-1.4091
32.0223-0.1557-0.66651.13080.11641.4279-0.0129-0.09630.06920.2252-0.03260.1642-0.0031-0.0260.04550.1131-0.01640.03170.1284-0.03020.123749.6851-23.973647.8254
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A14 - 501
2X-RAY DIFFRACTION2B9 - 501
3X-RAY DIFFRACTION3C14 - 501

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