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- PDB-6g3o: Crystal structure of human HDAC2 in complex with (R)-6-[3,4-Dioxo... -

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Basic information

Entry
Database: PDB / ID: 6g3o
TitleCrystal structure of human HDAC2 in complex with (R)-6-[3,4-Dioxo-2-(4-trifluoromethoxy-phenylamino)-cyclobut-1-enylamino]-heptanoic acid hydroxyamide
ComponentsHistone deacetylase 2
KeywordsHYDROLASE / HDAC inhibitors / Squaramide / HISTONE / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


positive regulation of male mating behavior / protein de-2-hydroxyisobutyrylase activity / protein lysine delactylase activity / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / negative regulation of dendritic spine development / histone decrotonylase activity / fungiform papilla formation / negative regulation of MHC class II biosynthetic process / behavioral response to ethanol ...positive regulation of male mating behavior / protein de-2-hydroxyisobutyrylase activity / protein lysine delactylase activity / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / negative regulation of dendritic spine development / histone decrotonylase activity / fungiform papilla formation / negative regulation of MHC class II biosynthetic process / behavioral response to ethanol / 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 / histone H4K16 deacetylase activity, hydrolytic mechanism / ESC/E(Z) complex / histone H4K5 deacetylase activity, hydrolytic mechanism / histone H4K8 deacetylase activity, hydrolytic mechanism / histone H3K4 deacetylase activity, hydrolytic mechanism / histone H3K14 deacetylase activity, hydrolytic mechanism / histone H4K12 deacetylase activity, hydrolytic mechanism / histone deacetylase / regulation of stem cell differentiation / cellular response to dopamine / cardiac muscle hypertrophy / STAT3 nuclear events downstream of ALK signaling / histone H3K9 deacetylase activity, hydrolytic mechanism / response to caffeine / protein lysine deacetylase activity / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / embryonic digit morphogenesis / histone deacetylase activity / positive regulation of intracellular estrogen receptor signaling pathway / Notch-HLH transcription pathway / Sin3-type complex / eyelid development in camera-type eye / positive regulation of stem cell population maintenance / dendrite development / odontogenesis of dentin-containing tooth / response to amyloid-beta / positive regulation of proteolysis / RNA Polymerase I Transcription Initiation / histone deacetylase complex / positive regulation of oligodendrocyte differentiation / Regulation of MECP2 expression and activity / positive regulation of collagen biosynthetic process / hair follicle placode formation / response to hyperoxia / NF-kappaB binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / progesterone receptor signaling pathway / 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 transforming growth factor beta stimulus / cellular response to retinoic acid / 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 / Regulation of PTEN gene transcription / Regulation of endogenous retroelements by KRAB-ZFP proteins / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / HDACs deacetylate histones / negative regulation of DNA-binding transcription factor activity / response to nicotine / promoter-specific chromatin binding / negative regulation of transforming growth factor beta receptor signaling pathway / circadian regulation of gene expression / response to cocaine / NoRC negatively regulates rRNA expression / protein modification process / NOTCH1 Intracellular Domain Regulates Transcription / cellular response to hydrogen peroxide / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / positive regulation of tumor necrosis factor production / heterochromatin formation / negative regulation of neuron projection development / Factors involved in megakaryocyte development and platelet production / cellular response to heat / RNA polymerase II-specific DNA-binding transcription factor binding / response to lipopolysaccharide / histone binding / Potential therapeutics for SARS / chromosome, telomeric region / chromatin remodeling / response to xenobiotic stimulus / negative regulation of DNA-templated transcription / positive regulation of cell population proliferation / chromatin binding / negative regulation of apoptotic process / chromatin / positive regulation of DNA-templated transcription / enzyme binding
Similarity search - Function
Histone deacetylase / Histone deacetylase domain / Arginase; Chain A / : / Histone deacetylase family / Histone deacetylase domain / Histone deacetylase domain superfamily / Histone deacetylase domain / Ureohydrolase domain superfamily / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-EL8 / Histone deacetylase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.27 Å
AuthorsIsabet, T. / Aurelly, M. / Chantalat, L. / Thoreau, E.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2018
Title: Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma.
Authors: Fournier, J.F. / Bhurruth-Alcor, Y. / Musicki, B. / Aubert, J. / Aurelly, M. / Bouix-Peter, C. / Bouquet, K. / Chantalat, L. / Delorme, M. / Drean, B. / Duvert, G. / Fleury-Bregeot, N. / ...Authors: Fournier, J.F. / Bhurruth-Alcor, Y. / Musicki, B. / Aubert, J. / Aurelly, M. / Bouix-Peter, C. / Bouquet, K. / Chantalat, L. / Delorme, M. / Drean, B. / Duvert, G. / Fleury-Bregeot, N. / Gauthier, B. / Grisendi, K. / Harris, C.S. / Hennequin, L.F. / Isabet, T. / Joly, F. / Lafitte, G. / Millois, C. / Morgentin, R. / Pascau, J. / Piwnica, D. / Rival, Y. / Soulet, C. / Thoreau, E. / Tomas, L.
History
DepositionMar 26, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 27, 2018Provider: repository / Type: Initial release
Revision 1.1Aug 29, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2May 8, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_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)129,52919
Polymers127,2733
Non-polymers2,25616
Water8,449469
1
A: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,9685
Polymers42,4241
Non-polymers5444
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4978
Polymers42,4241
Non-polymers1,0727
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Histone deacetylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,0646
Polymers42,4241
Non-polymers6405
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)92.050, 93.300, 139.420
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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


Mass: 42424.285 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

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Non-polymers , 8 types, 485 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-EL8 / (6~{R})-6-[[3,4-bis(oxidanylidene)-2-[[4-(trifluoromethyloxy)phenyl]amino]cyclobuten-1-yl]amino]-~{N}-oxidanyl-heptanamide


Mass: 415.364 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C18H20F3N3O5
#6: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


Mass: 238.278 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#7: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#8: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 469 / Source method: isolated from a natural source / Formula: H2O

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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: 2.35 Å3/Da / Density % sol: 47.7 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.1 M TRIS, pH 9.15, 54 %(w/v) PEG 400

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97856 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 1, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2.27→50 Å / Num. obs: 55580 / % possible obs: 99.1 % / Redundancy: 5.8 % / Biso Wilson estimate: 48.42 Å2 / CC1/2: 0.997 / Rrim(I) all: 0.132 / Net I/σ(I): 11.06
Reflection shellResolution: 2.27→2.41 Å / Redundancy: 5.7 % / Mean I/σ(I) obs: 1.98 / Num. unique obs: 48196 / CC1/2: 0.862 / Rrim(I) all: 0.783 / % possible all: 95.2

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
XDSdata reduction
Cootmodel building
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.27→33.26 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.917 / SU R Cruickshank DPI: 0.284 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.297 / SU Rfree Blow DPI: 0.205 / SU Rfree Cruickshank DPI: 0.204
RfactorNum. reflection% reflectionSelection details
Rfree0.219 2778 5 %RANDOM
Rwork0.172 ---
obs0.174 55562 99.2 %-
Displacement parametersBiso mean: 53.51 Å2
Baniso -1Baniso -2Baniso -3
1-11.344 Å20 Å20 Å2
2---15.391 Å20 Å2
3---4.0469 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: 1 / Resolution: 2.27→33.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8831 0 135 469 9435
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.019194HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0412419HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3190SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1603HARMONIC5
X-RAY DIFFRACTIONt_it9194HARMONIC20
X-RAY DIFFRACTIONt_nbd6SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.28
X-RAY DIFFRACTIONt_other_torsion17.42
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1112SEMIHARMONIC5
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_contact11016SEMIHARMONIC4
LS refinement shellResolution: 2.27→2.33 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3075 184 4.99 %
Rwork0.2445 3500 -
all0.2475 3684 -
obs--89.75 %
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)
11.73540.373-1.22050.5648-0.34152.4835-0.11360.324-0.12450.0767-0.045-0.02340.1779-0.08530.15860.01590.00630.03220.1918-0.0131-0.2099-13.0733-22.35181.3426
21.8062-0.40790.20860.69910.19831.3277-0.0583-0.2358-0.001-0.0541-0.00680.0861-0.0543-0.12180.06510.0238-0.009-0.011-0.0057-0.0292-0.1958-47.2016-9.310836.396
33.2651-0.37970.62271.4164-0.77892.27440.0794-0.4585-0.15670.1347-0.0971-0.1587-0.01260.24870.01770.0601-0.025-0.04570.17060.0455-0.1128-3.6134-24.406947.6024
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }

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