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- PDB-7sfc: Human DNMT1(729-1600) Bound to Zebularine-Containing 12mer dsDNA ... -

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Basic information

Entry
Database: PDB / ID: 7sfc
TitleHuman DNMT1(729-1600) Bound to Zebularine-Containing 12mer dsDNA and Inhibitor GSK3735967A
Components
  • (DNA (12-MER)) x 2
  • DNA (cytosine-5)-methyltransferase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / epigentics / DNA methytransferase fold / maintenance methylation / inhibition / DNA binding protein / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


chromosomal DNA methylation maintenance following DNA replication / negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching / epigenetic programming of gene expression / DNA-methyltransferase activity / negative regulation of vascular associated smooth muscle cell apoptotic process / cellular response to bisphenol A / DNA (cytosine-5-)-methyltransferase / DNA (cytosine-5-)-methyltransferase activity / SUMOylation of DNA methylation proteins / female germ cell nucleus ...chromosomal DNA methylation maintenance following DNA replication / negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching / epigenetic programming of gene expression / DNA-methyltransferase activity / negative regulation of vascular associated smooth muscle cell apoptotic process / cellular response to bisphenol A / DNA (cytosine-5-)-methyltransferase / DNA (cytosine-5-)-methyltransferase activity / SUMOylation of DNA methylation proteins / female germ cell nucleus / STAT3 nuclear events downstream of ALK signaling / methyl-CpG binding / DNA methylation-dependent constitutive heterochromatin formation / negative regulation of gene expression via chromosomal CpG island methylation / lncRNA binding / pericentric heterochromatin / Nuclear events stimulated by ALK signaling in cancer / positive regulation of vascular associated smooth muscle cell proliferation / DNA methylation / replication fork / PRC2 methylates histones and DNA / Defective pyroptosis / cellular response to amino acid stimulus / promoter-specific chromatin binding / NoRC negatively regulates rRNA expression / methylation / negative regulation of gene expression / DNA-templated transcription / positive regulation of gene expression / negative regulation of transcription by RNA polymerase II / mitochondrion / DNA binding / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
DNA (cytosine-5)-methyltransferase 1-like / DNA (cytosine-5)-methyltransferase 1, replication foci domain / Cytosine specific DNA methyltransferase replication foci domain / DMAP1-binding Domain / DMAP1-binding Domain / DMAP1-binding domain / DMAP1-binding domain profile. / : / DNA methylase, C-5 cytosine-specific, conserved site / C-5 cytosine-specific DNA methylases C-terminal signature. ...DNA (cytosine-5)-methyltransferase 1-like / DNA (cytosine-5)-methyltransferase 1, replication foci domain / Cytosine specific DNA methyltransferase replication foci domain / DMAP1-binding Domain / DMAP1-binding Domain / DMAP1-binding domain / DMAP1-binding domain profile. / : / DNA methylase, C-5 cytosine-specific, conserved site / C-5 cytosine-specific DNA methylases C-terminal signature. / CXXC zinc finger domain / Zinc finger, CXXC-type / Zinc finger CXXC-type profile. / DNA methylase, C-5 cytosine-specific, active site / C-5 cytosine-specific DNA methylases active site. / C-5 cytosine-specific DNA methylase (Dnmt) domain profile. / C-5 cytosine methyltransferase / C-5 cytosine-specific DNA methylase / Bromo adjacent homology domain / BAH domain / Bromo adjacent homology (BAH) domain / Bromo adjacent homology (BAH) domain superfamily / BAH domain profile. / Vaccinia Virus protein VP39 / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-I67 / DNA / DNA (> 10) / DNA (cytosine-5)-methyltransferase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.97 Å
AuthorsHorton, J.R. / Pathuri, S. / Cheng, X.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM134744 United States
CitationJournal: Structure / Year: 2022
Title: Structural characterization of dicyanopyridine containing DNMT1-selective, non-nucleoside inhibitors.
Authors: Horton, J.R. / Pathuri, S. / Wong, K. / Ren, R. / Rueda, L. / Fosbenner, D.T. / Heerding, D.A. / McCabe, M.T. / Pappalardi, M.B. / Zhang, X. / King, B.W. / Cheng, X.
History
DepositionOct 3, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 30, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 20, 2022Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jun 15, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 18, 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: DNA (cytosine-5)-methyltransferase 1
C: DNA (12-MER)
D: DNA (12-MER)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)108,98228
Polymers106,1473
Non-polymers2,83525
Water9,152508
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)161.733, 78.897, 117.335
Angle α, β, γ (deg.)90.000, 125.644, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Components on special symmetry positions
IDModelComponents
11D-906-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein DNA (cytosine-5)-methyltransferase 1 / Dnmt1 / CXXC-type zinc finger protein 9 / DNA methyltransferase HsaI / M.HsaI / MCMT


Mass: 98803.555 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DNMT1, AIM, CXXC9, DNMT / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Gold
References: UniProt: P26358, DNA (cytosine-5-)-methyltransferase

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DNA chain , 2 types, 2 molecules CD

#2: DNA chain DNA (12-MER)


Mass: 3678.407 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#3: DNA chain DNA (12-MER)


Mass: 3665.365 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)

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Non-polymers , 5 types, 533 molecules

#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-I67 / N-{[4-({[3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}methyl)phenyl]methyl}glycinamide


Mass: 477.625 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C25H31N7OS / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 19 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 508 / 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: 2.87 Å3/Da / Density % sol: 57.08 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 5.1
Details: 14-18% polyethylene glycol (PEG) 3350, 0.1 M citric acid (pH 5.1)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 29, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.97→35.35 Å / Num. obs: 80823 / % possible obs: 98.7 % / Redundancy: 6.1 % / Biso Wilson estimate: 32.7 Å2 / Rmerge(I) obs: 0.139 / Rpim(I) all: 0.06 / Net I/σ(I): 15.8
Reflection shellResolution: 1.97→2.06 Å / Rmerge(I) obs: 1.469 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 8006 / CC1/2: 0.442 / Rpim(I) all: 0.758 / % possible all: 98.2

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
SERGUIdata collection
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 6X9J

6x9j


Resolution: 1.97→35.35 Å / SU ML: 0.2336 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.2654
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.208 1997 2.47 %
Rwork0.1763 78826 -
obs0.1771 80823 95.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 45.08 Å2
Refinement stepCycle: LAST / Resolution: 1.97→35.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6533 487 186 508 7714
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0057473
X-RAY DIFFRACTIONf_angle_d0.755510216
X-RAY DIFFRACTIONf_chiral_restr0.04931077
X-RAY DIFFRACTIONf_plane_restr0.00641242
X-RAY DIFFRACTIONf_dihedral_angle_d15.62692765
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.97-2.020.3154810.28483203X-RAY DIFFRACTION54.64
2.02-2.080.29291450.25895728X-RAY DIFFRACTION97.75
2.08-2.140.26181450.24725737X-RAY DIFFRACTION97.46
2.14-2.210.28751430.23035636X-RAY DIFFRACTION96.35
2.21-2.290.24411460.21465813X-RAY DIFFRACTION99.4
2.29-2.380.26381490.19885875X-RAY DIFFRACTION99.85
2.38-2.480.23751490.19765868X-RAY DIFFRACTION99.83
2.48-2.620.23491480.19385868X-RAY DIFFRACTION99.85
2.62-2.780.22951490.19015829X-RAY DIFFRACTION99.19
2.78-2.990.20341460.18175794X-RAY DIFFRACTION98.3
2.99-3.290.22711460.17995732X-RAY DIFFRACTION97.24
3.3-3.770.17771490.15775903X-RAY DIFFRACTION99.49
3.77-4.750.17031510.13945906X-RAY DIFFRACTION99.65
4.75-35.350.17951500.15755934X-RAY DIFFRACTION98.14
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)
15.8781684682-0.6253724527322.303174317641.5802797595-0.3890323974612.47074901791-0.000948834417027-0.131830664089-0.1564448573140.0760131597747-0.0269132028662-0.290700673820.1676620140060.1723608563970.002697248743420.3720119963180.0813324983502-0.05540927712480.268149843105-0.05238804010370.2938883632115.30971758641-10.923091530428.947597427
20.314339809084-0.7575803690710.02800883540465.285639093310.2670507210970.8697003876720.0333935543905-0.1260157854890.3453002234760.01487909854180.0284946874919-0.7186198276-0.02404641860050.235452722683-0.06722012460250.288743188371-0.0652440124066-0.0371159387820.36205531448-0.05976048969510.330606170889-2.5237101144720.545538326531.3503759871
34.921073787912.10750334593-0.07936029406321.48303796574-0.190086761331-0.01714282118350.160602273888-0.5029641378720.507737466060.0904635078026-0.1395106656540.105592642629-0.126073512292-0.0159210847404-0.06329577952790.329370113027-0.025419834690.02310966701220.26259631632-0.07348247365370.293357067963-26.085089776826.15809586932.256725732
41.05834565931-0.3607034267380.01162575167770.4286465706110.1281127792970.8015525563980.0133000633702-0.00344015960767-0.0634751864961-0.04928125956260.07420788127080.0450176770330.0878587503785-0.0949278417357-0.07338314056930.263026094162-0.04704387194-0.03485896782680.1950481780560.03313029138940.170789395393-36.72975627683.3849969961820.5813772503
56.46212205894-2.33405669949-3.421161263144.849712077970.09405385090528.78971815419-0.1068843223720.973135049142-0.514783789731-0.8864041781660.4291054755880.5261872531380.03081720848180.374815025658-0.1932744188970.66878245956-0.0755549926312-0.1763686407470.4420981735850.08294110623340.534543325889-46.6386733406-8.7534221377131.4465074074
65.02662330062.261061677982.069735338553.439468893772.067637901147.804353700150.1943342794340.730976296557-1.00206425418-0.9437056019330.1758810602070.8783231935030.319083140694-0.769143524203-0.3484132573850.8943307208170.012213839151-0.3348586761251.06368071119-0.1156279908550.864340452426-46.066686054-8.3770594072630.455867519
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 730 through 878 )AA730 - 8781 - 149
22chain 'A' and (resid 879 through 951 )AA879 - 951150 - 222
33chain 'A' and (resid 952 through 1085 )AA952 - 1085223 - 356
44chain 'A' and (resid 1086 through 1600 )AA1086 - 1600357 - 842
55chain 'C' and (resid 1 through 12 )CAA1 - 12
66chain 'D' and (resid 13 through 24 )DAA13 - 24

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