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- PDB-7t7l: Structure of human G9a SET-domain (EHMT2) in complex with covalen... -

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Basic information

Entry
Database: PDB / ID: 7t7l
TitleStructure of human G9a SET-domain (EHMT2) in complex with covalent inhibitor (Compound 1)
ComponentsHistone-lysine N-methyltransferase EHMT2
KeywordsGENE REGULATION / G9a / Covalent inhibitor
Function / homology
Function and homology information


histone H3K56 methyltransferase activity / 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 ...histone H3K56 methyltransferase activity / 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 / C2H2 zinc finger domain binding / protein-lysine N-methyltransferase activity / 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 / RNA Polymerase I Transcription Initiation / Transcriptional Regulation by VENTX / spermatid development / behavioral response to cocaine / Transferases; Transferring one-carbon groups; Methyltransferases / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / cellular response to starvation / epigenetic regulation of gene expression / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / transcription corepressor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Regulation of TP53 Activity through Methylation / promoter-specific chromatin binding / PKMTs methylate histone lysines / p53 binding / Senescence-Associated Secretory Phenotype (SASP) / 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-G4R / Chem-G5U / S-ADENOSYLMETHIONINE / Histone-lysine N-methyltransferase EHMT2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsPark, K.-S. / Kumar, P.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01HD088626 United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of the First-in-Class G9a/GLP Covalent Inhibitors.
Authors: Park, K.S. / Xiong, Y. / Yim, H. / Velez, J. / Babault, N. / Kumar, P. / Liu, J. / Jin, J.
History
DepositionDec 15, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 6, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2022Group: 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 24, 2022Group: 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 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Mar 13, 2024Group: Source and taxonomy / Category: entity_src_gen
Revision 1.5Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)135,05328
Polymers130,4204
Non-polymers4,63324
Water6,215345
1
A: Histone-lysine N-methyltransferase EHMT2
C: Histone-lysine N-methyltransferase EHMT2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,52514
Polymers65,2102
Non-polymers2,31512
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2230 Å2
ΔGint-10 kcal/mol
Surface area25000 Å2
MethodPISA
2
B: Histone-lysine N-methyltransferase EHMT2
D: Histone-lysine N-methyltransferase EHMT2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,52714
Polymers65,2102
Non-polymers2,31712
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2220 Å2
ΔGint-11 kcal/mol
Surface area25570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.821, 72.303, 85.029
Angle α, β, γ (deg.)71.150, 86.170, 89.100
Int Tables number1
Space group name H-MP1

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Components

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Protein , 1 types, 4 molecules ABCD

#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.: 4 / Fragment: residues 913-1193
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EHMT2, BAT8, C6orf30, G9A, KMT1C, NG36 / Production host: Escherichia coli (E. coli)
References: UniProt: Q96KQ7, Transferases; Transferring one-carbon groups; Methyltransferases, histone-lysine N-methyltransferase

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Non-polymers , 5 types, 369 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-SAM / S-ADENOSYLMETHIONINE


Mass: 398.437 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C15H22N6O5S
#4: Chemical ChemComp-G5U / N-(6-methoxy-4-{[1-(propan-2-yl)piperidin-4-yl]amino}-7-[3-(pyrrolidin-1-yl)propoxy]quinazolin-2-yl)propanamide


Mass: 498.661 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C27H42N6O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-G4R / N-(6-methoxy-4-{[1-(propan-2-yl)piperidin-4-yl]amino}-7-[3-(pyrrolidin-1-yl)propoxy]quinazolin-2-yl)prop-2-enamide


Mass: 496.645 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H40N6O3 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 345 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.54 Å3/Da / Density % sol: 51.5 %
Crystal growTemperature: 290.15 K / Method: vapor diffusion, sitting drop
Details: 2% v/v 1,4-Dioxane, 10% w/v Polyethylene glycol 20,000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 7, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.959→80.299 Å / Num. all: 63720 / Num. obs: 63720 / % possible obs: 98.2 % / Redundancy: 2.4 % / Biso Wilson estimate: 31 Å2 / Rpim(I) all: 0.058 / Rrim(I) all: 0.089 / Rsym value: 0.067 / Net I/av σ(I): 8.3 / Net I/σ(I): 8.9 / Num. measured all: 152076
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2.2-2.322.40.4161.82221292130.3550.550.4162.497.4
2.32-2.462.40.2992.62115087730.2550.3950.2993.297.6
2.46-2.632.40.2033.81991582670.1740.2690.2034.297.9
2.63-2.842.40.1256.11851977300.1080.1660.125698.2
2.84-3.112.40.0818.81691370770.070.1080.0818.598.4
3.11-3.482.40.05112.81523664050.0440.0670.05112.698.7
3.48-4.022.30.0414.31344957290.0350.0540.0416.398.9
4.02-4.922.30.0412.71113647830.0360.0550.0418.999
4.92-6.962.40.03813.9878337330.0330.050.03818.899.1
6.96-68.4252.40.03814.3476320100.0330.0510.03820.297.9

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
SCALA3.3.22data scaling
PDB_EXTRACT3.27data extraction
MOLREPphasing
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5TTF

5ttf


Resolution: 2.2→68.425 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.96 / Phase error: 30.95 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2507 3096 4.86 %
Rwork0.2043 60551 -
obs0.2065 63647 98.08 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 95.72 Å2 / Biso mean: 44.2625 Å2 / Biso min: 21.76 Å2
Refinement stepCycle: final / Resolution: 2.2→68.425 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8565 0 267 345 9177
Biso mean--46 39.9 -
Num. residues----1065
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.2-2.23440.34471520.3094270897
2.2344-2.2710.39471390.2923274697
2.271-2.31020.33241420.287271898
2.3102-2.35220.33511420.283273297
2.3522-2.39750.34031540.27271798
2.3975-2.44640.33881460.261272497
2.4464-2.49960.3071260.2474279598
2.4996-2.55770.3291420.2524267398
2.5577-2.62170.2861510.236274798
2.6217-2.69260.24511410.2382277398
2.6926-2.77180.32441290.2393276398
2.7718-2.86130.33381390.2247277698
2.8613-2.96360.22951100.2227276598
2.9636-3.08220.28281530.2206276499
3.0822-3.22250.26841360.2148274199
3.2225-3.39240.2231520.2133279499
3.3924-3.60490.2351320.2042275699
3.6049-3.88320.23521510.1839276199
3.8832-4.2740.20661400.1645278999
4.274-4.89230.20751380.1527278799
4.8923-6.16310.18451570.1574277299

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