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

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Basic information

Entry
Database: PDB / ID: 7sfd
TitleHuman DNMT1(729-1600) Bound to Zebularine-Containing 12mer dsDNA and Inhibitor GSK3543105A
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. / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
Chem-IO5 / S-ADENOSYL-L-HOMOCYSTEINE / DNA / DNA (> 10) / DNA (cytosine-5)-methyltransferase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.09 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)107,49812
Polymers106,1473
Non-polymers1,3509
Water4,522251
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)161.598, 77.416, 116.514
Angle α, β, γ (deg.)90.000, 125.762, 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

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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 , 6 types, 260 molecules

#4: Chemical ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


Type: L-peptide linking / Mass: 384.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H20N6O5S
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#8: Chemical ChemComp-IO5 / (2S)-2-({3,5-dicyano-4-ethyl-6-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]pyridin-2-yl}sulfanyl)-2-phenylacetamide


Mass: 464.583 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H28N6O2S / Feature type: SUBJECT OF INVESTIGATION
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 251 / 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: 2.79 Å3/Da / Density % sol: 55.85 %
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 22, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.09→41.81 Å / Num. obs: 130375 / % possible obs: 96.4 % / Redundancy: 3.5 % / Biso Wilson estimate: 38.67 Å2 / Rmerge(I) obs: 0.109 / Rpim(I) all: 0.066 / Net I/σ(I): 12
Reflection shellResolution: 2.09→2.16 Å / Rmerge(I) obs: 1.106 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 11962 / CC1/2: 0.298 / Rpim(I) all: 0.817 / % possible all: 89

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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: 2.09→41.81 Å / SU ML: 0.2707 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.7038
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2159 3877 2.98 %
Rwork0.185 126226 -
obs0.186 130103 96.08 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 60.91 Å2
Refinement stepCycle: LAST / Resolution: 2.09→41.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6414 487 85 251 7237
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00527239
X-RAY DIFFRACTIONf_angle_d0.73169954
X-RAY DIFFRACTIONf_chiral_restr0.04641081
X-RAY DIFFRACTIONf_plane_restr0.0071214
X-RAY DIFFRACTIONf_dihedral_angle_d19.06552601
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.09-2.120.34571190.32933839X-RAY DIFFRACTION82.25
2.12-2.140.34451260.31694153X-RAY DIFFRACTION88.41
2.14-2.170.29831260.29964071X-RAY DIFFRACTION87.64
2.17-2.20.24851320.27654285X-RAY DIFFRACTION90.46
2.2-2.230.34141400.2694503X-RAY DIFFRACTION95.95
2.23-2.270.30381380.26074511X-RAY DIFFRACTION97.81
2.27-2.30.24141420.25074627X-RAY DIFFRACTION97.67
2.3-2.340.28781410.23444639X-RAY DIFFRACTION98.03
2.34-2.380.2551430.23844576X-RAY DIFFRACTION98.79
2.38-2.420.28521430.22794661X-RAY DIFFRACTION98.42
2.42-2.470.31911410.23284546X-RAY DIFFRACTION97.97
2.47-2.520.25271440.22984638X-RAY DIFFRACTION98.15
2.52-2.570.2861410.21464624X-RAY DIFFRACTION97.84
2.57-2.630.26721430.20924586X-RAY DIFFRACTION98.11
2.63-2.70.23821420.20664621X-RAY DIFFRACTION98.37
2.7-2.770.20391430.18924634X-RAY DIFFRACTION98.74
2.77-2.850.23881400.19854621X-RAY DIFFRACTION98.33
2.86-2.950.20461400.19324561X-RAY DIFFRACTION97.15
2.95-3.050.19981340.20154429X-RAY DIFFRACTION95.38
3.05-3.170.26191320.2024383X-RAY DIFFRACTION92.63
3.17-3.320.20781440.19094659X-RAY DIFFRACTION99.09
3.32-3.490.21051410.17114663X-RAY DIFFRACTION99.69
3.49-3.710.23661460.17324684X-RAY DIFFRACTION99.4
3.71-40.20221440.15654597X-RAY DIFFRACTION98.79
4-4.40.1531420.14154615X-RAY DIFFRACTION98
4.4-5.040.1661340.13764547X-RAY DIFFRACTION96.65
5.04-6.340.20471310.16754312X-RAY DIFFRACTION91.74
6.34-41.810.15781450.15614641X-RAY DIFFRACTION98.78
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)
16.69527362726-0.5399304121613.293670371471.53981411399-1.082744159333.69148986070.04108807143230.0615806489764-0.28655375147-0.0189062107936-0.137046049945-0.3004610686840.198415354930.4364055456010.07576056158280.4905174909660.176030150097-0.04710687449550.478786183634-0.04668366304450.4015973496155.39084790808-8.6780996435229.0674308334
23.995710546940.3279813479750.9422393943661.18470210229-0.2153226157821.69056706794-0.387355933623-0.7368413130841.739592680520.06037370687040.09544947244950.174788191284-0.3544771125740.04769435240350.08404978704120.455812107689-0.0220183346938-0.06506721272960.428214629654-0.2075202360150.709926368863-22.422682712227.143274698433.7814841668
32.58386605643-0.4303342342690.3863944760211.759214820531.349482177012.022677281590.04820779783820.274698375783-0.2753303893330.1263133265060.05259453151-0.01871921965810.1834630548270.0872571890974-0.07388996264640.444164534679-0.0458569564131-0.04822911387220.317218442803-0.016979086560.221415033135-26.435387136-3.167666583746.81903246019
43.07009826874-1.066744491760.6668038345651.146865064410.09268766497581.5959608146-0.0125605857115-0.396047880184-0.3547478107130.0883260226040.1951603481810.2386689283360.208318327604-0.324222699606-0.0782921896370.34185886674-0.0845575951568-0.01699019715750.2832119248210.1141049753090.217209255048-40.33356163384.5046141170724.4726078319
56.39130992684-4.18909541135-0.4873119712377.47405488729-0.7470224995079.79088032302-0.4720201861520.158997115561-0.560697159263-0.4751935460471.111900388310.2174779462230.2288386746390.092842304879-0.5063444112071.01516084832-0.196821939272-0.4224616329990.5425996888030.2245029904181.15842650702-45.7769656054-9.4748925003430.1583444438
63.094555937620.4153215518060.9309420193777.041235017024.83698512893.480878593480.3430412376090.244316237603-1.53356428044-0.6590210269860.7957703936530.05919483753810.773864085673-0.240996897028-1.20174006671.11083847521-0.303584992225-0.3653543029911.27315177234-0.0456277137891.32597233759-45.1308659074-8.791351362729.5899265422
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 729 through 906 )AA729 - 9061 - 178
22chain 'A' and (resid 907 through 1097 )AA907 - 1097179 - 369
33chain 'A' and (resid 1098 through 1258 )AA1098 - 1258370 - 500
44chain 'A' and (resid 1259 through 1600 )AA1259 - 1600501 - 842
55chain 'C' and (resid 1 through 12 )CK1 - 12
66chain 'D' and (resid 13 through 24 )DN13 - 24

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