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- PDB-7zzp: Structure of HDAC2 complexed with an inhibitory ligand -

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Basic information

Entry
Database: PDB / ID: 7zzp
TitleStructure of HDAC2 complexed with an inhibitory ligand
ComponentsHistone deacetylase 2
KeywordsTRANSCRIPTION / Deacetylase / chromatin binding / transcription regulator
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
(2S)-2-HYDROXYPROPANOIC ACID / 6-methyl-4-oxidanyl-pyran-2-one / DI(HYDROXYETHYL)ETHER / TRIETHYLENE GLYCOL / Histone deacetylase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.52 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 25, 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 2.0Nov 15, 2023Group: Atomic model / Data collection / Category: atom_site / chem_comp_atom / chem_comp_bond / Item: _atom_site.auth_atom_id / _atom_site.label_atom_id

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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)172,99239
Polymers169,6813
Non-polymers3,31236
Water15,097838
1
A: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,42813
Polymers56,5601
Non-polymers86712
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,35216
Polymers56,5601
Non-polymers1,79115
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,21310
Polymers56,5601
Non-polymers6539
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)93.247, 98.847, 140.770
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 , 12 types, 874 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-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H14O4
#6: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical
ChemComp-KJ6 / 6-methyl-4-oxidanyl-pyran-2-one


Mass: 126.110 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H6O3 / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-2OP / (2S)-2-HYDROXYPROPANOIC ACID


Mass: 90.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H6O3
#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-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O3
#11: 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
#12: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#13: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 838 / 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: 1.91 Å3/Da / Density % sol: 35.66 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 39% PEG 300 0.1M pH=8.4 CHES/NaOH

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92819 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Aug 4, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92819 Å / Relative weight: 1
ReflectionResolution: 1.52→80.9 Å / Num. obs: 199750 / % possible obs: 100 % / Redundancy: 6.6 % / Rrim(I) all: 0.086 / Net I/σ(I): 11.8
Reflection shellResolution: 1.52→1.55 Å / Num. unique obs: 11114 / Rrim(I) all: 0.749

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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: 1.52→80.9 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.963 / SU B: 2.396 / SU ML: 0.042 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.061 / ESU R Free: 0.062 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1736 9932 5 %RANDOM
Rwork0.1531 ---
obs0.1541 189620 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 75.89 Å2 / Biso mean: 22.558 Å2 / Biso min: 7.7 Å2
Baniso -1Baniso -2Baniso -3
1--0.1 Å20 Å20 Å2
2--0.29 Å2-0 Å2
3----0.19 Å2
Refinement stepCycle: final / Resolution: 1.52→80.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8888 0 416 838 10142
Biso mean--35.74 32.15 -
Num. residues----1103
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0159411
X-RAY DIFFRACTIONr_bond_other_d0.0010.0178313
X-RAY DIFFRACTIONr_angle_refined_deg1.3851.75912662
X-RAY DIFFRACTIONr_angle_other_deg0.5181.75319504
X-RAY DIFFRACTIONr_dihedral_angle_1_deg9.5055.4381164
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.80921.222442
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.0215.1571496
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.751552
X-RAY DIFFRACTIONr_chiral_restr0.0720.21131
X-RAY DIFFRACTIONr_gen_planes_refined0.0010.0210541
X-RAY DIFFRACTIONr_gen_planes_other00.021843
LS refinement shellResolution: 1.52→1.559 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.258 713 -
Rwork0.24 13867 -
all-14580 -
obs--100 %
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)
10.6577-0.1662-0.39151.0143-0.06711.2643-0.0409-0.0415-0.025-0.0628-0.0057-0.01790.03530.04910.04650.0216-0.0120.01690.0699-0.00630.016912.5709-23.1389-1.5982
21.2565-0.37910.02420.6785-0.11491.10510.0044-0.073-0.00250.0166-0.0187-0.05070.03290.06070.01430.007-0.0123-0.00440.04010.01120.00641.1644-38.726837.1059
31.74760.1173-0.27761.27270.24311.03410.0492-0.19690.0920.1827-0.1070.17380.0395-0.07290.05780.0498-0.03780.03150.1631-0.05010.08350.0534-24.183548.3341
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A11 - 503
2X-RAY DIFFRACTION2B13 - 503
3X-RAY DIFFRACTION3C13 - 503

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