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- PDB-7xua: Structure of G9a in complex with compound 10a -

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Basic information

Entry
Database: PDB / ID: 7xua
TitleStructure of G9a in complex with compound 10a
ComponentsHistone-lysine N-methyltransferase EHMT2
KeywordsTRANSFERASE / histone lysine methyltransferase / inhibitor / protein-inhibitor complex
Function / homology
Function and homology information


regulation of protein modification process / phenotypic switching / neuron fate specification / [histone H3]-lysine9 N-methyltransferase / peptidyl-lysine dimethylation / histone H3K9 methyltransferase activity / histone H3K9me2 methyltransferase activity / histone H3K27 methyltransferase activity / synaptonemal complex assembly / negative regulation of autophagosome assembly ...regulation of protein modification process / phenotypic switching / neuron fate specification / [histone H3]-lysine9 N-methyltransferase / peptidyl-lysine dimethylation / histone H3K9 methyltransferase activity / histone H3K9me2 methyltransferase activity / histone H3K27 methyltransferase activity / synaptonemal complex assembly / negative regulation of autophagosome assembly / oocyte development / histone H3K56 methyltransferase activity / protein-lysine N-methyltransferase activity / C2H2 zinc finger domain binding / fertilization / cellular response to cocaine / organ growth / DNA methylation-dependent constitutive heterochromatin formation / negative regulation of gene expression via chromosomal CpG island methylation / Transcriptional Regulation by E2F6 / regulation of DNA replication / behavioral response to cocaine / RNA Polymerase I Transcription Initiation / Transcriptional Regulation by VENTX / spermatid development / long-term memory / response to fungicide / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / Transferases; Transferring one-carbon groups; Methyltransferases / cellular response to starvation / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / transcription corepressor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / promoter-specific chromatin binding / Regulation of TP53 Activity through Methylation / PKMTs methylate histone lysines / p53 binding / cellular response to xenobiotic stimulus / Senescence-Associated Secretory Phenotype (SASP) / response to ethanol / nuclear speck / chromatin / negative regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
Histone-lysine N-methyltransferase EHMT2 / Histone-lysine N-methyltransferase EHMT1/EHMT2 / : / Histone-lysine N-methyltransferase EHMT1/EHMT2, Cys-rich region / Pre-SET motif / Pre-SET domain / Pre-SET domain profile. / N-terminal to some SET domains / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain ...Histone-lysine N-methyltransferase EHMT2 / Histone-lysine N-methyltransferase EHMT1/EHMT2 / : / Histone-lysine N-methyltransferase EHMT1/EHMT2, Cys-rich region / Pre-SET motif / Pre-SET domain / Pre-SET domain profile. / N-terminal to some SET domains / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain / SET domain superfamily / SET domain profile. / SET domain / Ankyrin repeat / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily
Similarity search - Domain/homology
Chem-I5X / SINEFUNGIN / Histone-lysine N-methyltransferase EHMT2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.87 Å
AuthorsNiwa, H. / Shirai, F. / Sato, S. / Nishigaya, Y. / Umehara, T.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS) Japan
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of Novel Substrate-Competitive Lysine Methyltransferase G9a Inhibitors as Anticancer Agents.
Authors: Nishigaya, Y. / Takase, S. / Sumiya, T. / Kikuzato, K. / Sato, T. / Niwa, H. / Sato, S. / Nakata, A. / Sonoda, T. / Hashimoto, N. / Namie, R. / Honma, T. / Umehara, T. / Shirouzu, M. / ...Authors: Nishigaya, Y. / Takase, S. / Sumiya, T. / Kikuzato, K. / Sato, T. / Niwa, H. / Sato, S. / Nakata, A. / Sonoda, T. / Hashimoto, N. / Namie, R. / Honma, T. / Umehara, T. / Shirouzu, M. / Koyama, H. / Yoshida, M. / Ito, A. / Shirai, F.
History
DepositionMay 18, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 29, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone-lysine N-methyltransferase EHMT2
B: Histone-lysine N-methyltransferase EHMT2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,59117
Polymers65,2102
Non-polymers2,38115
Water6,936385
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3080 Å2
ΔGint3 kcal/mol
Surface area25890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.552, 77.844, 70.094
Angle α, β, γ (deg.)90.000, 91.742, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Histone-lysine N-methyltransferase EHMT2 / Euchromatic histone-lysine N-methyltransferase 2 / HLA-B-associated transcript 8 / Histone H3-K9 ...Euchromatic histone-lysine N-methyltransferase 2 / HLA-B-associated transcript 8 / Histone H3-K9 methyltransferase 3 / H3-K9-HMTase 3 / Lysine N-methyltransferase 1C / Protein G9a


Mass: 32604.924 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Description: Cell-free synthesis / Gene: EHMT2, BAT8, C6orf30, G9A, KMT1C, NG36 / Production host: Escherichia coli (E. coli)
References: UniProt: Q96KQ7, Transferases; Transferring one-carbon groups; Methyltransferases

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Non-polymers , 6 types, 400 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-SFG / SINEFUNGIN / ADENOSYL-ORNITHINE


Mass: 381.387 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H23N7O5
#4: Chemical ChemComp-I5X / ~{N}-[(1~{S})-1-(1~{H}-benzimidazol-2-yl)-3-methylsulfanyl-propyl]-3,6,6-trimethyl-4-oxidanylidene-5,7-dihydro-1~{H}-indole-2-carboxamide


Mass: 424.559 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H28N4O2S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER


Mass: 122.143 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H12NO3 / Comment: pH buffer*YM
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 385 / 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: 2.36 Å3/Da / Density % sol: 47.99 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1M Bis-Tris propane (pH7.5), 0.2M Sodium Formate, 10% Ethylene Glycol, 23.5% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL38B1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 6, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.87→50 Å / Num. obs: 49368 / % possible obs: 98.8 % / Redundancy: 7.3 % / Biso Wilson estimate: 24.38 Å2 / Rsym value: 0.1 / Net I/σ(I): 18.6
Reflection shellResolution: 1.87→1.94 Å / Mean I/σ(I) obs: 2 / Num. unique obs: 4528 / Rsym value: 0.66

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158+SVNrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3RJW

3rjw


Resolution: 1.87→34.02 Å / SU ML: 0.2222 / Cross valid method: FREE R-VALUE / σ(F): 0.76 / Phase error: 26.783
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2244 2477 5.03 %
Rwork0.1871 91042 -
obs0.1891 49265 97.43 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 43.29 Å2
Refinement stepCycle: LAST / Resolution: 1.87→34.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4393 0 138 385 4916
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00664630
X-RAY DIFFRACTIONf_angle_d0.97536268
X-RAY DIFFRACTIONf_chiral_restr0.051661
X-RAY DIFFRACTIONf_plane_restr0.0073815
X-RAY DIFFRACTIONf_dihedral_angle_d14.28521733
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.87-1.890.41241150.31732317X-RAY DIFFRACTION74.35
1.89-1.920.32471340.30642603X-RAY DIFFRACTION84.84
1.92-1.940.32191750.30022822X-RAY DIFFRACTION88.35
1.94-1.960.30951440.28782832X-RAY DIFFRACTION91.71
1.96-1.990.31831220.26672931X-RAY DIFFRACTION94.55
1.99-2.020.2561670.25753097X-RAY DIFFRACTION96.77
2.02-2.050.28061700.26312962X-RAY DIFFRACTION97.51
2.05-2.080.3261830.24553092X-RAY DIFFRACTION98.79
2.08-2.110.28761510.24453097X-RAY DIFFRACTION99.08
2.11-2.140.28221460.2443108X-RAY DIFFRACTION99.88
2.14-2.180.32481760.23083160X-RAY DIFFRACTION99.91
2.18-2.220.2931610.22893058X-RAY DIFFRACTION99.88
2.22-2.260.22791510.21413128X-RAY DIFFRACTION99.3
2.26-2.310.2181720.21173072X-RAY DIFFRACTION99.97
2.31-2.360.27091620.20413128X-RAY DIFFRACTION99.79
2.36-2.410.27091870.19963053X-RAY DIFFRACTION99.91
2.41-2.470.26621550.20773154X-RAY DIFFRACTION99.82
2.47-2.540.2512190.20743073X-RAY DIFFRACTION99.91
2.54-2.620.25521500.20313120X-RAY DIFFRACTION99.97
2.62-2.70.23741730.19263087X-RAY DIFFRACTION99.82
2.7-2.80.23511460.19943114X-RAY DIFFRACTION99.91
2.8-2.910.26541280.19983173X-RAY DIFFRACTION99.97
2.91-3.040.26851410.19113100X-RAY DIFFRACTION99.85
3.04-3.20.20071650.18323129X-RAY DIFFRACTION99.82
3.2-3.40.18661810.17233081X-RAY DIFFRACTION100
3.4-3.660.16171770.15973104X-RAY DIFFRACTION99.94
3.66-4.030.1931670.14433144X-RAY DIFFRACTION100
4.03-4.610.17851810.12893084X-RAY DIFFRACTION100
4.61-5.810.17331470.14283114X-RAY DIFFRACTION99.94
5.81-34.020.19571740.16343105X-RAY DIFFRACTION99.7
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)
10.6394010236680.617219307984-0.5840675633732.02297848085-0.5333591102531.95884864874-0.209756050562-0.605845143794-0.2115159784430.04227480511380.3316633597230.5807730145370.193141811442-0.280069050011-0.09201456113790.2741969278360.07807176492030.02038776237360.4620465540440.2232036636860.431735218717-14.1982832408-8.5756938962636.0330738783
21.490488823180.720913973167-0.4774311959260.375630293095-0.1079338935161.001123189070.060626275863-1.252708456110.3157527971220.2586642664220.0152569008503-0.166160984775-0.08599276940080.9029086496530.1914236521740.296036431260.0769996718239-0.04230586163441.02542994747-0.1088368021320.30259032350115.27933131363.7252265581239.4614335195
31.623408526090.3988598398210.1131101561931.03018051474-0.5717585771411.3184155885-0.0832861313119-1.36287510925-0.08579774526180.2753346962950.1450729540290.1364295715120.004168288997010.4437975934050.0188831113690.3319142988430.1422707619660.03138967345130.7794322010440.05678238519730.2392096082872.80751834151-2.4077804672243.5080304509
40.1327520504970.4351843750450.247321478144.68208611024-0.9923675517991.463667672360.188406213229-0.6983742838610.3874872576470.651531666520.2483976303360.249436471839-0.7075538719380.476020058647-0.3171305660260.5334968778220.03682120887640.1390675269320.822108515305-0.2454116685360.42622236455-5.7766456015513.432613667944.6579694262
52.245386541610.2189023734660.09084133605660.6052119889530.2510365422620.368919666479-0.0662962143873-1.579104107750.2238602581510.430315284980.2594726091110.238366147569-0.09168005906210.38854159316-0.08208465595710.3396113995220.1327864764560.06187924732560.879762706973-0.02761753346250.258134278774-1.781824970511.284047090145.7342030227
63.281052858170.4048560420541.70537838090.37677502984-0.3174467817681.79989491688-0.399712545096-0.8880739680860.5282814931240.3608567272340.08445503909330.134256018893-0.147919257926-0.151650324585-0.07420294158290.8337312517250.2842163795850.2810162419571.252719643620.0634095937280.560648330267-14.75408525794.639245675861.8105350211
76.83326893205-0.140939537782-1.762605906142.09052145555-0.9217489272763.18428809341-0.297862667193-0.405173041228-0.7288757738660.2944824390750.296876962905-0.5156650832970.3185415931830.5477660854510.04797289897620.2690060783480.0621893152017-0.008496882114850.385883855291-0.01161518786380.39866793694824.6441840108-10.136535637521.8368233743
84.27626354878-1.25275069612-1.479709346760.8437862447350.2017688735580.602363885404-0.0512542048044-0.8047677252610.1482694174640.1478728324170.209945318815-0.281227582625-0.05389171809330.40011325173-0.189826431820.200530169683-0.00649793896721-0.01247101080460.31662937168-0.09345344413950.29606100398929.0004903781-3.5914469536619.165645199
92.73192616448-0.123642118225-0.1617074888820.1924880029160.4992034250161.05375261234-0.0700837258234-0.3246513359940.457755860209-0.1833174963520.126778747874-4.88586329346E-5-0.356378423882-0.000309587802349-0.04912062358770.2543953197430.02305899085570.01272366241590.20403782318-0.03001913196150.318982091514-2.652137651185.4266959275920.4010905329
104.20695252297-0.523133778253-0.9972675960240.9591652772190.3087428605470.943027941128-0.02896235871950.365457100805-0.351060640414-0.1496114524680.03572968054140.06104427462340.0136971388408-0.0622327584356-0.007532160902030.24544001541-0.0120302047452-0.01421172688330.182522810827-0.031695303090.2221492063196.31912722214-5.3466795753711.5522012006
112.2015376741-0.380664289459-0.2777004428092.775150611541.160942964063.056326220850.09095221909270.1168580831580.595735561412-0.1815869424910.150764241169-0.259489076031-0.4728476494680.209436654371-0.2486853669080.283758130567-0.06736844789260.05732083001170.218409862954-0.04865487690840.33470953726418.63061366799.1534686903112.003938335
121.87452579986-0.644845345211-0.6210767963441.191246396061.167071520182.143269714080.1440720552320.09608247372680.675474864673-0.177422583610.0920296478929-0.0680819862386-0.4600973519980.119483119854-0.1691463607060.276490718598-0.0222632803930.03456874487160.147892064397-0.03636074826410.2823127959985.787468720784.5701624352912.991924187
131.681772875330.2652496136660.4786054681170.8784806242570.4554816478151.10871004535-0.02654989672190.698102923587-0.500708691332-0.3101209888750.05346742876890.07268689517350.2187764368960.068259460365-0.0007595867874910.283361310231-0.03157064727280.02070236058650.32672597388-0.1458835222420.29501020553717.6382918976-7.76725140063.51689119915
142.92994721279-0.245177299898-0.965838575171.9187888945-0.8634709042054.90931172323-0.05723171338490.7899871099520.284451547471-0.325906976984-0.13240440259-0.0574233553796-0.205221525510.272394237670.1756376375920.477914889018-0.03908748877080.1173806101510.6056100168510.03957438161410.44323183574927.15876450456.15291143199-7.49820290659
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 916 through 954 )AA916 - 9541 - 39
22chain 'A' and (resid 955 through 1001 )AA955 - 100140 - 86
33chain 'A' and (resid 1002 through 1078 )AA1002 - 107887 - 163
44chain 'A' and (resid 1079 through 1096 )AA1079 - 1096164 - 181
55chain 'A' and (resid 1097 through 1155 )AA1097 - 1155182 - 240
66chain 'A' and (resid 1156 through 1188 )AA1156 - 1188241 - 273
77chain 'B' and (resid 917 through 935 )BH917 - 9351 - 19
88chain 'B' and (resid 936 through 954 )BH936 - 95420 - 38
99chain 'B' and (resid 955 through 985 )BH955 - 98539 - 69
1010chain 'B' and (resid 986 through 1069 )BH986 - 106970 - 153
1111chain 'B' and (resid 1070 through 1118 )BH1070 - 1118154 - 200
1212chain 'B' and (resid 1119 through 1140 )BH1119 - 1140201 - 222
1313chain 'B' and (resid 1141 through 1155 )BH1141 - 1155223 - 237
1414chain 'B' and (resid 1156 through 1192 )BH1156 - 1192238 - 274

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