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- PDB-7zzt: Ligand binding to HDAC2 -

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Basic information

Entry
Database: PDB / ID: 7zzt
TitleLigand 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-KJF / DI(HYDROXYETHYL)ETHER / TRIETHYLENE GLYCOL / Histone deacetylase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.56 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 / Refinement description
Category: citation / citation_author / pdbx_refine_tls_group
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 / _pdbx_refine_tls_group.end_auth_seq_id
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)172,01725
Polymers169,6813
Non-polymers2,33622
Water18,3031016
1
A: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,2858
Polymers56,5601
Non-polymers7247
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,74811
Polymers56,5601
Non-polymers1,18810
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,9846
Polymers56,5601
Non-polymers4245
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)92.208, 98.023, 139.275
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 , 10 types, 1038 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-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#7: Chemical ChemComp-KJF / [(2~{R})-1-oxidanylidene-4-phenyl-1-pyrrolidin-1-yl-butan-2-yl]azanium


Mass: 233.329 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C14H21N2O / Feature type: SUBJECT OF INVESTIGATION
#8: 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
#9: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#10: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1016 / 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: 1.85 Å3/Da / Density % sol: 33.68 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 40% PEG 300 0.1M pH=8.6 CHES/NaOH

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.97242 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97242 Å / Relative weight: 1
ReflectionResolution: 1.557→48.39 Å / Num. obs: 177099 / % possible obs: 98.5 % / Redundancy: 6.1 % / Rrim(I) all: 0.077 / Net I/σ(I): 11.1
Reflection shellResolution: 1.557→1.59 Å / Mean I/σ(I) obs: 1.8 / Num. unique obs: 8730 / Rrim(I) all: 0.928

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Processing

Software
NameVersionClassification
REFMAC5.8.0222refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.56→48.39 Å / Cor.coef. Fo:Fc: 0.976 / Cor.coef. Fo:Fc free: 0.966 / SU B: 3.121 / SU ML: 0.052 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.066 / ESU R Free: 0.068 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1733 8843 5 %RANDOM
Rwork0.148 ---
obs0.1492 168789 98.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 82.33 Å2 / Biso mean: 26.338 Å2 / Biso min: 11.06 Å2
Baniso -1Baniso -2Baniso -3
1--0.72 Å20 Å20 Å2
2--2.21 Å2-0 Å2
3----1.49 Å2
Refinement stepCycle: final / Resolution: 1.56→48.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8879 0 311 1016 10206
Biso mean--33.15 39.84 -
Num. residues----1102
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0159355
X-RAY DIFFRACTIONr_bond_other_d0.0010.0178268
X-RAY DIFFRACTIONr_angle_refined_deg1.4291.75712616
X-RAY DIFFRACTIONr_angle_other_deg0.5161.73919422
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.5845.2851157
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.31821.159447
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.71715.1661504
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.171552
X-RAY DIFFRACTIONr_chiral_restr0.0760.21134
X-RAY DIFFRACTIONr_gen_planes_refined0.0010.02110500
X-RAY DIFFRACTIONr_gen_planes_other00.021844
LS refinement shellResolution: 1.56→1.597 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.298 575 -
Rwork0.298 10951 -
obs--87.2 %
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)
10.7527-0.1664-0.4061.08920.00671.3358-0.0197-0.0354-0.0205-0.0528-0.0199-0.00420.03280.05440.03960.0733-0.0180.01710.0291-0.00790.074712.5308-23.0128-1.4505
21.5734-0.43950.03980.7568-0.12871.12660.0036-0.0686-0.01270.0041-0.0156-0.05190.0260.05840.0120.056-0.013-0.00050.01170.01070.0671.112-38.474436.6141
31.7891-0.1057-0.37651.15010.22711.03910.0144-0.11630.03860.1526-0.05890.13180.0409-0.03620.04450.106-0.02040.02040.074-0.03190.133849.5404-23.920947.8585
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A11 - 607
2X-RAY DIFFRACTION2B14 - 610
3X-RAY DIFFRACTION3C13 - 605

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