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- PDB-6mbp: GLP Methyltransferase with Inhibitor EML741- P3121 Crystal Form -

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Basic information

Entry
Database: PDB / ID: 6mbp
TitleGLP Methyltransferase with Inhibitor EML741- P3121 Crystal Form
ComponentsHistone-lysine N-methyltransferase EHMT1
KeywordsTRANSFERASE/TRANSFERASE INHBITOR / Histone / H3 / Methylation Inhibition / TRANSFERASE / TRANSFERASE-TRANSFERASE INHBITOR complex
Function / homology
Function and homology information


[histone H3]-lysine9 N-methyltransferase / peptidyl-lysine monomethylation / peptidyl-lysine dimethylation / histone H3K27 methyltransferase activity / histone H3K9 methyltransferase activity / histone H3K9me2 methyltransferase activity / protein-lysine N-methyltransferase activity / C2H2 zinc finger domain binding / DNA methylation-dependent constitutive heterochromatin formation / Transcriptional Regulation by E2F6 ...[histone H3]-lysine9 N-methyltransferase / peptidyl-lysine monomethylation / peptidyl-lysine dimethylation / histone H3K27 methyltransferase activity / histone H3K9 methyltransferase activity / histone H3K9me2 methyltransferase activity / protein-lysine N-methyltransferase activity / C2H2 zinc finger domain binding / DNA methylation-dependent constitutive heterochromatin formation / Transcriptional Regulation by E2F6 / regulation of embryonic development / Transcriptional Regulation by VENTX / response to fungicide / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / transcription corepressor binding / Transferases; Transferring one-carbon groups; Methyltransferases / methyltransferase activity / Regulation of TP53 Activity through Methylation / PKMTs methylate histone lysines / p53 binding / chromatin organization / positive regulation of cold-induced thermogenesis / Senescence-Associated Secretory Phenotype (SASP) / nuclear body / negative regulation of DNA-templated transcription / chromatin / negative regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
Histone-lysine N-methyltransferase EHMT1 / 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 / Beta-clip-like / SET domain ...Histone-lysine N-methyltransferase EHMT1 / 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 / Beta-clip-like / SET domain / Ankyrin repeats (many copies) / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain / SET domain superfamily / SET domain profile. / SET domain / 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-JDG / S-ADENOSYL-L-HOMOCYSTEINE / Histone-lysine N-methyltransferase EHMT1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.947 Å
AuthorsHorton, J.R. / Cheng, X.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM049245-23 United States
CitationJournal: J. Med. Chem. / Year: 2019
Title: Discovery of a Novel Chemotype of Histone Lysine Methyltransferase EHMT1/2 (GLP/G9a) Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Co-crystal Structure.
Authors: Milite, C. / Feoli, A. / Horton, J.R. / Rescigno, D. / Cipriano, A. / Pisapia, V. / Viviano, M. / Pepe, G. / Amendola, G. / Novellino, E. / Cosconati, S. / Cheng, X. / Castellano, S. / Sbardella, G.
History
DepositionAug 30, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 27, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 11, 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 EHMT1
B: Histone-lysine N-methyltransferase EHMT1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,54926
Polymers60,4652
Non-polymers3,08424
Water7,458414
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4960 Å2
ΔGint-34 kcal/mol
Surface area24360 Å2
Unit cell
Length a, b, c (Å)95.510, 95.510, 147.201
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Histone-lysine N-methyltransferase EHMT1 / Euchromatic histone-lysine N-methyltransferase 1 / Eu-HMTase1 / G9a-like protein 1 / GLP1 / Histone ...Euchromatic histone-lysine N-methyltransferase 1 / Eu-HMTase1 / G9a-like protein 1 / GLP1 / Histone H3-K9 methyltransferase 5 / H3-K9-HMTase 5 / Lysine N-methyltransferase 1D


Mass: 30232.373 Da / Num. of mol.: 2 / Fragment: residues 1006-1266
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EHMT1, EUHMTASE1, GLP, KIAA1876, KMT1D / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: Q9H9B1, histone-lysine N-methyltransferase

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Non-polymers , 5 types, 438 molecules

#2: Chemical ChemComp-JDG / 2-cyclohexyl-7-methoxy-N-[1-(propan-2-yl)piperidin-4-yl]-8-[3-(pyrrolidin-1-yl)propoxy]-3H-1,4-benzodiazepin-5-amine


Mass: 523.753 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H49N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


Type: L-peptide linking / Mass: 384.411 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H20N6O5S
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 414 / 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: 3.21 Å3/Da / Density % sol: 61.63 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 15% PEG 4000, 20% isopropanol and 100mM citrate (pH 5.5)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 23, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.947→45.424 Å / Num. obs: 109623 / % possible obs: 99.9 % / Redundancy: 9.7 % / Rmerge(I) obs: 0.115 / Rpim(I) all: 0.038 / Net I/σ(I): 20.8
Reflection shellResolution: 1.947→2.02 Å / Redundancy: 7.8 % / Mean I/σ(I) obs: 2.8 / Num. unique obs: 10961 / CC1/2: 0.836 / Rpim(I) all: 0.396 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3FPD

3fpd


Resolution: 1.947→45.424 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 18.56
RfactorNum. reflection% reflection
Rfree0.1816 3817 3.48 %
Rwork0.1608 --
obs0.1616 109564 99.64 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.947→45.424 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4175 0 184 414 4773
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0064575
X-RAY DIFFRACTIONf_angle_d0.8476196
X-RAY DIFFRACTIONf_dihedral_angle_d16.2712741
X-RAY DIFFRACTIONf_chiral_restr0.054632
X-RAY DIFFRACTIONf_plane_restr0.005811
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9473-1.97190.2721270.27643638X-RAY DIFFRACTION92
1.9719-1.99790.25181400.24863920X-RAY DIFFRACTION100
1.9979-2.02530.2161420.24483925X-RAY DIFFRACTION100
2.0253-2.05420.25811420.22933894X-RAY DIFFRACTION100
2.0542-2.08480.24781440.23043961X-RAY DIFFRACTION100
2.0848-2.11740.23671480.21813972X-RAY DIFFRACTION100
2.1174-2.15210.23351370.20363894X-RAY DIFFRACTION100
2.1521-2.18920.22381430.20763890X-RAY DIFFRACTION100
2.1892-2.22910.19281420.19393951X-RAY DIFFRACTION100
2.2291-2.27190.21331460.19273935X-RAY DIFFRACTION100
2.2719-2.31830.21021400.173914X-RAY DIFFRACTION100
2.3183-2.36870.16571440.17453920X-RAY DIFFRACTION100
2.3687-2.42380.21221400.17863874X-RAY DIFFRACTION100
2.4238-2.48440.21811400.17093970X-RAY DIFFRACTION100
2.4844-2.55160.21031420.17333965X-RAY DIFFRACTION100
2.5516-2.62670.19671410.15733923X-RAY DIFFRACTION100
2.6267-2.71140.18831430.16183929X-RAY DIFFRACTION100
2.7114-2.80830.19271430.16483945X-RAY DIFFRACTION100
2.8083-2.92070.22141390.16873916X-RAY DIFFRACTION100
2.9207-3.05360.221420.15853902X-RAY DIFFRACTION100
3.0536-3.21460.16661420.16543950X-RAY DIFFRACTION100
3.2146-3.41590.20481390.14833933X-RAY DIFFRACTION100
3.4159-3.67960.15391410.13973930X-RAY DIFFRACTION100
3.6796-4.04970.14531450.13283906X-RAY DIFFRACTION100
4.0497-4.63520.13031410.11993936X-RAY DIFFRACTION100
4.6352-5.83790.12921450.12753937X-RAY DIFFRACTION100
5.8379-45.43670.17131390.15433917X-RAY DIFFRACTION100
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)
14.7909-0.1833-4.61476.48210.61824.2917-0.03060.81330.0642-0.75260.1099-0.25220.164-0.2984-0.04770.364-0.0218-0.01910.3757-0.0070.2521-39.625811.80790.9986
21.27131.9558-3.33453.9762-4.18558.7913-0.370.0097-0.198-0.4283-0.0755-0.63010.84230.33740.40390.31790.04120.0360.2311-0.03120.2708-30.75610.22243.7346
32.2193-0.6287-0.61342.0363-0.06391.13160.0382-0.1070.32520.23770.0888-0.1409-0.14430.0652-0.11970.26270.02050.00320.1995-0.03650.2153-48.584630.03623.2271
49.6076-3.453-7.44961.53362.52515.9776-0.14190.24140.11940.04660.0354-0.05780.1211-0.12170.09530.23420.01220.02440.20270.01020.2033-43.139623.4588.5602
52.9175-0.1546-0.06382.8204-1.89263.7589-0.0934-0.39320.06270.3868-0.0016-0.3586-0.21690.31910.10130.22390.0253-0.02360.2043-0.03780.2004-32.355119.359917.9275
63.0388-0.072-1.53251.7292-0.46463.94710.1133-0.05350.28420.08070.06-0.1647-0.28350.1766-0.18190.2023-0.006-0.02250.1405-0.01640.1841-35.355926.952714.0946
78.3535-1.37051.63357.3585-3.19672.78120.058-0.18470.41610.6218-0.3658-1.1724-0.70621.24380.27960.3213-0.0824-0.08540.5115-0.00120.4406-17.877728.309812.3419
86.75270.2148-0.59731.3449-0.25513.4324-0.14110.0160.1690.24780.02810.9677-0.2271-0.41950.09930.33480.10570.08180.2091-0.0090.5447-72.400319.780721.8451
94.7539-5.1195-4.70915.21274.69854.0862-0.4695-0.52630.05420.71840.4335-0.13750.31640.23180.02280.37240.0503-0.00480.27120.03430.2664-47.58318.194130.1731
107.70221.7167-0.38533.64590.36961.586-0.16950.2712-0.4383-0.06420.13640.0640.16620.01260.03990.23630.04240.00030.1398-0.01370.1759-52.0663-5.179913.018
119.4128-6.1716-0.30035.4597-0.19020.70020.10360.5930.2672-0.306-0.08070.3357-0.1427-0.4424-0.01490.2280.0342-0.03010.27640.04560.2646-58.60085.668610.9391
123.6463-0.01270.90863.12241.11184.1589-0.0108-0.4513-0.2790.59870.03980.72170.1978-0.1666-0.05640.33160.04640.15590.19930.06130.4122-67.27557.349629.2431
134.4296-0.60650.4522.68320.17571.88220.0457-0.0963-0.53470.1867-0.02480.76360.1328-0.2498-0.01880.26440.01330.05820.1720.01250.3956-66.97611.241322.9713
147.79771.2283.9633.7312.0638.50120.4811-0.8443-0.78571.2314-0.35171.47460.8641-1.2867-0.13170.6124-0.15650.29030.53740.11040.8896-79.6192-2.321234.606
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 975 through 992 )
2X-RAY DIFFRACTION2chain 'A' and (resid 993 through 1011 )
3X-RAY DIFFRACTION3chain 'A' and (resid 1012 through 1078 )
4X-RAY DIFFRACTION4chain 'A' and (resid 1079 through 1106 )
5X-RAY DIFFRACTION5chain 'A' and (resid 1107 through 1163 )
6X-RAY DIFFRACTION6chain 'A' and (resid 1164 through 1212 )
7X-RAY DIFFRACTION7chain 'A' and (resid 1213 through 1235 )
8X-RAY DIFFRACTION8chain 'B' and (resid 976 through 1011 )
9X-RAY DIFFRACTION9chain 'B' and (resid 1012 through 1027 )
10X-RAY DIFFRACTION10chain 'B' and (resid 1028 through 1082 )
11X-RAY DIFFRACTION11chain 'B' and (resid 1083 through 1096 )
12X-RAY DIFFRACTION12chain 'B' and (resid 1097 through 1163 )
13X-RAY DIFFRACTION13chain 'B' and (resid 1164 through 1212 )
14X-RAY DIFFRACTION14chain 'B' and (resid 1213 through 1235 )

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