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- PDB-7zzw: Ligand binding to HDAC2 -

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Basic information

Entry
Database: PDB / ID: 7zzw
TitleLigand binding to HDAC2
ComponentsHistone deacetylase 2
KeywordsTRANSCRIPTION / protein deacetylation / transcriptional repressor complex / chromatin binding
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-KKW / 2-(cyclohexylazaniumyl)ethanesulfonate / DI(HYDROXYETHYL)ETHER / Histone deacetylase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.73 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)173,10231
Polymers169,6813
Non-polymers3,42128
Water9,134507
1
A: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,89811
Polymers56,5601
Non-polymers1,33710
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,66411
Polymers56,5601
Non-polymers1,10410
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,5409
Polymers56,5601
Non-polymers9808
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)92.149, 97.934, 139.538
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, 535 molecules

#2: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C4H10O3
#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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#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-KKW / [(2~{R},4~{S})-4-(3-chlorophenyl)pyrrolidin-2-yl]-(4-thieno[2,3-c]pyridin-7-ylpiperazin-1-yl)methanone


Mass: 426.962 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C22H23ClN4OS / Feature type: SUBJECT OF INVESTIGATION
#9: Chemical ChemComp-KZF / 2-(cyclohexylazaniumyl)ethanesulfonate


Mass: 207.290 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H17NO3S / Comment: pH buffer*YM
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 507 / 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: 1.86 Å3/Da / Density % sol: 33.7 %
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: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 10, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.64→48.41 Å / Num. obs: 132203 / % possible obs: 98.8 % / Redundancy: 3.92 % / Rrim(I) all: 0.095 / Net I/σ(I): 6.46
Reflection shellResolution: 1.64→1.74 Å / Num. unique obs: 42988 / Rrim(I) all: 0.824

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Processing

Software
NameVersionClassification
REFMAC5.8.0232refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
XDSdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.73→48.41 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.963 / SU B: 4.606 / SU ML: 0.073 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.097 / ESU R Free: 0.092 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1891 6751 5.1 %RANDOM
Rwork0.1643 ---
obs0.1656 125241 99.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 94.29 Å2 / Biso mean: 31.794 Å2 / Biso min: 10 Å2
Baniso -1Baniso -2Baniso -3
1-0.72 Å20 Å2-0 Å2
2---1.39 Å20 Å2
3---0.67 Å2
Refinement stepCycle: final / Resolution: 1.73→48.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8884 0 359 507 9750
Biso mean--47.2 36.1 -
Num. residues----1102
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0159382
X-RAY DIFFRACTIONr_bond_other_d0.0010.0178208
X-RAY DIFFRACTIONr_angle_refined_deg1.4081.75812642
X-RAY DIFFRACTIONr_angle_other_deg0.5041.75219271
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.7415.3651152
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.17421.047445
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.76915.1361504
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.4011551
X-RAY DIFFRACTIONr_chiral_restr0.0720.21133
X-RAY DIFFRACTIONr_gen_planes_refined0.0010.02110462
X-RAY DIFFRACTIONr_gen_planes_other00.021820
LS refinement shellResolution: 1.73→1.774 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.284 468 -
Rwork0.295 9061 -
obs--98.35 %
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)
11.7404-0.4940.06920.9313-0.3051.4118-0.00410.0023-0.0152-0.02-0.0306-0.06640.0440.05670.03470.0066-0.01870.00130.0880.00650.00670.9832-38.281836.6685
20.7878-0.2668-0.35241.37960.03241.3875-0.0437-0.0576-0.0282-0.0284-0.0203-0.01150.04720.04420.0640.0199-0.02070.01690.1454-0.01030.016112.6766-22.9738-1.2719
32.1059-0.0603-0.39861.30620.23641.3290.0281-0.12180.09370.197-0.04760.1196-0.003-0.02350.01960.0506-0.01910.02280.1861-0.01970.080749.6203-23.830747.848
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A13 - 602
2X-RAY DIFFRACTION2B12 - 602
3X-RAY DIFFRACTION3C13 - 602

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