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- PDB-5tuy: Structure of human G9a SET-domain (EHMT2) in complex with inhibit... -

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Basic information

Entry
Database: PDB / ID: 5tuy
TitleStructure of human G9a SET-domain (EHMT2) in complex with inhibitor MS0124
ComponentsHistone-lysine N-methyltransferase EHMT2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Methyl-TRANSFERASE INHIBITOR complex / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


regulation of protein modification process / histone H3K56 methyltransferase activity / : / phenotypic switching / neuron fate specification / : / [histone H3]-lysine9 N-methyltransferase / histone H3K27 methyltransferase activity / histone H3K9 methyltransferase activity / histone H3K9me2 methyltransferase activity ...regulation of protein modification process / histone H3K56 methyltransferase activity / : / phenotypic switching / neuron fate specification / : / [histone H3]-lysine9 N-methyltransferase / histone H3K27 methyltransferase activity / histone H3K9 methyltransferase activity / histone H3K9me2 methyltransferase activity / peptidyl-lysine dimethylation / synaptonemal complex assembly / negative regulation of autophagosome assembly / oocyte development / protein-lysine N-methyltransferase activity / C2H2 zinc finger domain binding / fertilization / : / cellular response to cocaine / : / organ growth / Transcriptional Regulation by E2F6 / spermatid development / behavioral response to cocaine / regulation of DNA replication / RNA Polymerase I Transcription Initiation / Transcriptional Regulation by VENTX / long-term memory / response to fungicide / Transferases; Transferring one-carbon groups; Methyltransferases / cellular response to starvation / transcription corepressor binding / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / promoter-specific chromatin binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Regulation of TP53 Activity through Methylation / PKMTs methylate histone lysines / cellular response to xenobiotic stimulus / p53 binding / 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 domain / Pre-SET motif / Pre-SET domain profile. / N-terminal to some SET domains / Beta-clip-like / SET domain ...Histone-lysine N-methyltransferase EHMT2 / Histone-lysine N-methyltransferase EHMT1/EHMT2 / : / Histone-lysine N-methyltransferase EHMT1/EHMT2, Cys-rich region / Pre-SET domain / Pre-SET motif / Pre-SET domain profile. / N-terminal to some SET domains / Beta-clip-like / SET domain / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily / SET domain / SET domain profile. / SET domain / Ankyrin repeat / Beta Complex / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Mainly Beta
Similarity search - Domain/homology
Chem-7L6 / S-ADENOSYLMETHIONINE / Histone-lysine N-methyltransferase EHMT2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsBabault, N. / Xiong, Y. / Liu, J. / Jin, J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM103893 United States
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase.
Authors: Xiong, Y. / Li, F. / Babault, N. / Dong, A. / Zeng, H. / Wu, H. / Chen, X. / Arrowsmith, C.H. / Brown, P.J. / Liu, J. / Vedadi, M. / Jin, J.
History
DepositionNov 7, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 22, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 22, 2017Group: Database references
Revision 1.2Sep 27, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id

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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)63,87714
Polymers61,7822
Non-polymers2,09512
Water1,820101
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2270 Å2
ΔGint-7 kcal/mol
Surface area25310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.970, 82.300, 73.740
Angle α, β, γ (deg.)90.000, 89.970, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A
21chain B

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111chain AA921 - 2000
211chain BB923 - 2000

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Components

#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: 30890.984 Da / Num. of mol.: 2 / Fragment: UNP residues 887-1154
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EHMT2, BAT8, C6orf30, G9A, KMT1C, NG36 / Plasmid: pET28a-LIC / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) codon plus RIL
References: UniProt: Q96KQ7, Transferases; Transferring one-carbon groups; Methyltransferases, histone-lysine N-methyltransferase
#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE / S-Adenosyl methionine


Mass: 398.437 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H22N6O5S
#4: Chemical ChemComp-7L6 / 6,7-dimethoxy-N-(1-methylpiperidin-4-yl)-2-(morpholin-4-yl)quinazolin-4-amine


Mass: 387.476 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H29N5O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 101 / 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: 2.81 Å3/Da / Density % sol: 56.24 %
Crystal growTemperature: 290 K / Method: vapor diffusion / pH: 6.5
Details: 20% (w/v) PEG 3,350, 0.2 M NaF, 0.1 M Bis-Tris propane (pH 6.5)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.9792 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 4, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.6→73.74 Å / Num. obs: 21095 / % possible obs: 100 % / Redundancy: 3.9 % / Biso Wilson estimate: 31.15 Å2 / CC1/2: 0.595 / Net I/σ(I): 4.9
Reflection shellResolution: 2.6→2.74 Å / % possible obs: 100 % / Redundancy: 3.9 % / Mean I/uI all: 1.8 / Num. unique obs: 3083 / CC1/2: 0.968

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Processing

Software
NameVersionClassification
SCALAdata scaling
PHENIX1.9_1692refinement
PDB_EXTRACT3.2data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3K5K

3k5k


Resolution: 2.6→56.97 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.45
RfactorNum. reflection% reflection
Rfree0.2339 1124 5.33 %
Rwork0.1711 --
obs0.1745 21071 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 115.44 Å2 / Biso mean: 34.3351 Å2 / Biso min: 13.37 Å2
Refinement stepCycle: final / Resolution: 2.6→56.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4262 0 118 101 4481
Biso mean--31.04 25.64 -
Num. residues----530
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0124511
X-RAY DIFFRACTIONf_angle_d1.2166060
X-RAY DIFFRACTIONf_chiral_restr0.055637
X-RAY DIFFRACTIONf_plane_restr0.006788
X-RAY DIFFRACTIONf_dihedral_angle_d13.7941686
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2486X-RAY DIFFRACTION4.204TORSIONAL
12B2486X-RAY DIFFRACTION4.204TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 8 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.6001-2.71840.32411330.269525012634
2.7184-2.86170.29931280.239824922620
2.8617-3.0410.30991320.225224642596
3.041-3.27580.27711560.20724702626
3.2758-3.60540.24491410.177124852626
3.6054-4.1270.23281320.146525062638
4.127-5.1990.17141460.118625022648
5.199-56.98370.18031560.133425272683
Refinement TLS params.Method: refined / Origin x: 19.0606 Å / Origin y: -2.9056 Å / Origin z: 16.4431 Å
111213212223313233
T0.1667 Å2-0.0002 Å20.0408 Å2-0.1365 Å20.009 Å2--0.2134 Å2
L1.4367 °2-0.1196 °21.5239 °2-0.4771 °2-0.1119 °2--2.4712 °2
S0.0383 Å °0.0169 Å °-0.0521 Å °0.009 Å °0.0518 Å °0.0272 Å °0.0361 Å °-0.1365 Å °-0.0759 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA921 - 2000
2X-RAY DIFFRACTION1allB923 - 2000
3X-RAY DIFFRACTION1allC1 - 2
4X-RAY DIFFRACTION1allS1 - 156

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