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- PDB-6mbo: GLP Methyltransferase with Inhibitor EML741-P212121 Crystal Form -

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Basic information

Entry
Database: PDB / ID: 6mbo
TitleGLP Methyltransferase with Inhibitor EML741-P212121 Crystal Form
ComponentsHistone-lysine N-methyltransferase EHMT1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Histone / H3 / Methylation Inhibition / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


[histone H3]-lysine9 N-methyltransferase / peptidyl-lysine monomethylation / peptidyl-lysine dimethylation / histone H3K9 methyltransferase activity / histone H3K9me2 methyltransferase activity / facultative heterochromatin formation / histone H3K27 methyltransferase activity / protein-lysine N-methyltransferase activity / C2H2 zinc finger domain binding / DNA methylation-dependent constitutive heterochromatin formation ...[histone H3]-lysine9 N-methyltransferase / peptidyl-lysine monomethylation / peptidyl-lysine dimethylation / histone H3K9 methyltransferase activity / histone H3K9me2 methyltransferase activity / facultative heterochromatin formation / histone H3K27 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 / Transferases; Transferring one-carbon groups; Methyltransferases / transcription corepressor binding / 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: 1.591 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)64,72130
Polymers60,4652
Non-polymers4,25628
Water10,629590
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5250 Å2
ΔGint-25 kcal/mol
Surface area24560 Å2
Unit cell
Length a, b, c (Å)87.732, 88.306, 95.124
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, 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
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, 618 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.: 4 / 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.: 14 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 590 / 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: 3.05 Å3/Da / Density % sol: 59.63 %
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: 1.59→40.05 Å / Num. obs: 174976 / % possible obs: 91.4 % / Redundancy: 6.9 % / Rmerge(I) obs: 0.149 / Rpim(I) all: 0.056 / Net I/σ(I): 12.7
Reflection shellResolution: 1.59→1.65 Å / Redundancy: 3.4 % / Mean I/σ(I) obs: 2 / Num. unique obs: 13524 / Rpim(I) all: 0.507 / % possible all: 80.7

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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: 1.591→40.049 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 21.07
RfactorNum. reflection% reflection
Rfree0.194 3820 2.19 %
Rwork0.1807 --
obs0.1811 174575 91.06 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.591→40.049 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4142 0 268 590 5000
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024564
X-RAY DIFFRACTIONf_angle_d0.6486165
X-RAY DIFFRACTIONf_dihedral_angle_d8.0093618
X-RAY DIFFRACTIONf_chiral_restr0.043623
X-RAY DIFFRACTIONf_plane_restr0.003788
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5909-1.6110.278790.31784400X-RAY DIFFRACTION63
1.611-1.63220.27351540.28894833X-RAY DIFFRACTION70
1.6322-1.65460.3282910.27685025X-RAY DIFFRACTION72
1.6546-1.67820.2964680.26665298X-RAY DIFFRACTION75
1.6782-1.70320.25752120.25585307X-RAY DIFFRACTION77
1.7032-1.72990.231820.25065527X-RAY DIFFRACTION79
1.7299-1.75820.2262460.23795781X-RAY DIFFRACTION82
1.7582-1.78850.26032540.235708X-RAY DIFFRACTION84
1.7885-1.82110.24141310.2265994X-RAY DIFFRACTION86
1.8211-1.85610.2502450.22396346X-RAY DIFFRACTION90
1.8561-1.8940.22912660.22296288X-RAY DIFFRACTION93
1.894-1.93520.25181140.22926674X-RAY DIFFRACTION95
1.9352-1.98020.1949820.21936822X-RAY DIFFRACTION97
1.9802-2.02970.23972240.21096789X-RAY DIFFRACTION99
2.0297-2.08460.26331580.20596928X-RAY DIFFRACTION100
2.0846-2.14590.1897940.19836989X-RAY DIFFRACTION100
2.1459-2.21520.2262250.1926835X-RAY DIFFRACTION100
2.2152-2.29430.22471480.18466976X-RAY DIFFRACTION100
2.2943-2.38620.2262980.1846992X-RAY DIFFRACTION100
2.3862-2.49480.21941940.18346856X-RAY DIFFRACTION99
2.4948-2.62630.19542130.17946693X-RAY DIFFRACTION98
2.6263-2.79080.2754180.16967095X-RAY DIFFRACTION100
2.7908-3.00620.18312410.16526860X-RAY DIFFRACTION100
3.0062-3.30860.19511810.16116907X-RAY DIFFRACTION100
3.3086-3.7871000000000.14617104X-RAY DIFFRACTION100
3.787-4.770.13524020.13056672X-RAY DIFFRACTION100
4.77-40.06171000000000.1537056X-RAY DIFFRACTION99
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)
12.90080.3132-0.45797.71130.1592.4919-0.0443-0.2088-0.48240.27380.09420.62790.2879-0.2692-0.03570.1128-0.00950.02120.17040.04340.2418-21.3204-27.406129.497
21.1842-0.1960.09462.1185-0.47022.71250.06460.15140.079-0.0895-0.0398-0.08790.01670.1755-0.0250.06670.02830.00950.0999-0.00440.1099-12.4473-2.927610.8984
33.6121-2.00450.15575.1238-0.05592.38380.28450.3447-0.1756-0.4389-0.2162-0.21910.31320.2172-0.06210.20280.075-0.00710.1985-0.02440.0914-11.064-13.4853.1672
41.5594-2.31041.93966.7975-2.28452.44530.24170.1033-0.4252-0.0980.08860.54530.079-0.2087-0.31270.12660.0017-0.04650.1539-0.00810.1636-20.1408-16.07638.9098
51.5003-0.3268-0.07453.6315-0.43682.0376-0.0133-0.044-0.1437-0.07660.04020.01750.1289-0.0039-0.03580.07160.0249-0.02080.10050.00180.1197-11.1702-25.113122.7005
65.951-1.43642.25846.00551.67186.1331-0.18690.00690.18670.07540.1243-0.7175-0.08120.47270.02880.0990.025-0.04480.1069-0.01560.1449-3.2704-15.461727.0788
70.3845-0.48710.33954.3457-1.58810.78030.08980.0629-0.0224-0.2964-0.067-0.01760.12830.0506-0.01630.08660.0197-0.01590.122-0.02490.0878-7.3784-18.714316.4669
82.8318-0.95880.53772.0543-0.41852.61990.08750.2736-0.3156-0.2825-0.0104-0.06220.21840.1446-0.08520.16630.04180.00150.1028-0.02190.1418-3.6851-29.710418.7266
92.13411.79183.91127.91923.11887.94110.0830.1269-0.1635-0.39780.0251-0.43080.30620.3276-0.06840.18360.0730.02690.15870.00640.18273.3805-35.939922.8436
1010.0271-6.82056.312.1907-5.34787.44570.1570.5844-0.1415-0.3506-0.1240.1174-0.0833-0.1354-0.16820.2410.0399-0.04670.2343-0.04310.142-33.3741-0.34524.1651
117.55820.02754.71930.78930.04784.7721-0.0230.72620.4505-0.3702-0.0849-0.1209-0.389-0.02390.10270.2370.09450.02230.26590.04680.1057-29.11828.12945.7559
121.58850.20520.54492.5137-0.72241.53240.0989-0.3695-0.13050.3923-0.01530.1166-0.04310.0366-0.08040.16680.05910.01650.1477-0.00870.131-22.7527-5.787934.5313
133.1181-1.54990.12184.8283-0.39391.948-0.1283-0.3865-0.17570.3740.20560.5062-0.1086-0.2545-0.05570.11980.01390.04520.18590.03870.1348-35.1965-3.959633.7059
143.4489-2.61622.77034.1484-2.63032.41040.22380.1719-0.3004-0.3204-0.06380.44550.3171-0.0488-0.18830.11470.0066-0.0280.12810.00020.1871-34.5678-7.901123.4774
152.8996-0.37790.00632.2427-0.1572.10180.08750.22470.2513-0.2091-0.03830.0811-0.161-0.1942-0.02630.12180.05560.00310.12020.00880.1142-34.6588.693114.426
168.7031.799-1.06227.84660.60912.41280.0778-0.54571.0050.8023-0.0123-0.2536-0.3940.141-0.06850.22080.0366-0.00010.179-0.07760.3294-24.525916.466322.1124
171.6877-0.81880.40781.9055-0.37061.8320.003-0.05130.10450.00940.01470.1001-0.0996-0.147-0.01170.06620.00370.00540.097-0.01490.1002-33.73848.133921.0668
187.4883.11120.84586.55561.52063.26460.1546-0.07081.2696-0.0332-0.07470.1358-0.3942-0.2045-0.05720.20010.06690.03330.1579-0.00710.3686-40.127824.203518.6585
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 975 through 1011 )
2X-RAY DIFFRACTION2chain 'A' and (resid 1012 through 1042 )
3X-RAY DIFFRACTION3chain 'A' and (resid 1043 through 1082 )
4X-RAY DIFFRACTION4chain 'A' and (resid 1083 through 1096 )
5X-RAY DIFFRACTION5chain 'A' and (resid 1097 through 1136 )
6X-RAY DIFFRACTION6chain 'A' and (resid 1137 through 1163 )
7X-RAY DIFFRACTION7chain 'A' and (resid 1164 through 1197 )
8X-RAY DIFFRACTION8chain 'A' and (resid 1198 through 1219 )
9X-RAY DIFFRACTION9chain 'A' and (resid 1220 through 1235 )
10X-RAY DIFFRACTION10chain 'B' and (resid 976 through 995 )
11X-RAY DIFFRACTION11chain 'B' and (resid 996 through 1015 )
12X-RAY DIFFRACTION12chain 'B' and (resid 1016 through 1042 )
13X-RAY DIFFRACTION13chain 'B' and (resid 1043 through 1082 )
14X-RAY DIFFRACTION14chain 'B' and (resid 1083 through 1096 )
15X-RAY DIFFRACTION15chain 'B' and (resid 1097 through 1136 )
16X-RAY DIFFRACTION16chain 'B' and (resid 1137 through 1153 )
17X-RAY DIFFRACTION17chain 'B' and (resid 1154 through 1212 )
18X-RAY DIFFRACTION18chain 'B' and (resid 1213 through 1235 )

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