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- PDB-6x9i: Human DNMT1(729-1600) Bound to Zebularine-Containing 12mer dsDNA -

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Basic information

Entry
Database: PDB / ID: 6x9i
TitleHuman DNMT1(729-1600) Bound to Zebularine-Containing 12mer dsDNA
Components
  • DNA (5'-D(*GP*AP*GP*GP*CP*(5CM)P*GP*CP*CP*TP*GP*C)-3')
  • DNA (5'-D(*GP*CP*AP*GP*G)-R(P*(PYO))-D(P*GP*GP*CP*CP*TP*C)-3')
  • DNA (cytosine-5)-methyltransferase 1
KeywordsTRANSFERASE / EPIGENETICS / DNA METHYLTRANSFERASE FOLD / MAINTENANCE METHYLATION
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 / DNA (cytosine-5-)-methyltransferase activity / cellular response to bisphenol A / DNA (cytosine-5-)-methyltransferase activity, acting on CpN substrates / DNA (cytosine-5-)-methyltransferase activity, acting on CpNpG substrates / DNA (cytosine-5-)-methyltransferase ...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 / DNA (cytosine-5-)-methyltransferase activity / cellular response to bisphenol A / DNA (cytosine-5-)-methyltransferase activity, acting on CpN substrates / DNA (cytosine-5-)-methyltransferase activity, acting on CpNpG substrates / DNA (cytosine-5-)-methyltransferase / 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
S-ADENOSYL-L-HOMOCYSTEINE / DNA / DNA (> 10) / DNA (cytosine-5)-methyltransferase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsPathuri, S. / Horton, J.R. / 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: Nat Cancer / Year: 2021
Title: Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia.
Authors: Pappalardi, M.B. / Keenan, K. / Cockerill, M. / Kellner, W.A. / Stowell, A. / Sherk, C. / Wong, K. / Pathuri, S. / Briand, J. / Steidel, M. / Chapman, P. / Groy, A. / Wiseman, A.K. / McHugh, ...Authors: Pappalardi, M.B. / Keenan, K. / Cockerill, M. / Kellner, W.A. / Stowell, A. / Sherk, C. / Wong, K. / Pathuri, S. / Briand, J. / Steidel, M. / Chapman, P. / Groy, A. / Wiseman, A.K. / McHugh, C.F. / Campobasso, N. / Graves, A.P. / Fairweather, E. / Werner, T. / Raoof, A. / Butlin, R.J. / Rueda, L. / Horton, J.R. / Fosbenner, D.T. / Zhang, C. / Handler, J.L. / Muliaditan, M. / Mebrahtu, M. / Jaworski, J.P. / McNulty, D.E. / Burt, C. / Eberl, H.C. / Taylor, A.N. / Ho, T. / Merrihew, S. / Foley, S.W. / Rutkowska, A. / Li, M. / Romeril, S.P. / Goldberg, K. / Zhang, X. / Kershaw, C.S. / Bantscheff, M. / Jurewicz, A.J. / Minthorn, E. / Grandi, P. / Patel, M. / Benowitz, A.B. / Mohammad, H.P. / Gilmartin, A.G. / Prinjha, R.K. / Ogilvie, D. / Carpenter, C. / Heerding, D. / Baylin, S.B. / Jones, P.A. / Cheng, X. / King, B.W. / Luengo, J.I. / Jordan, A.M. / Waddell, I. / Kruger, R.G. / McCabe, M.T.
History
DepositionJun 2, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 7, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 19, 2022Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Dec 25, 2024Group: Advisory / Data collection ...Advisory / Data collection / Derived calculations / Other / Structure summary
Category: chem_comp / pdbx_database_status ...chem_comp / pdbx_database_status / pdbx_entry_details / pdbx_modification_feature / pdbx_struct_sheet_hbond / pdbx_validate_close_contact / struct_conn / struct_sheet / struct_sheet_order / struct_sheet_range
Item: _chem_comp.mon_nstd_flag / _chem_comp.type ..._chem_comp.mon_nstd_flag / _chem_comp.type / _pdbx_database_status.pdb_format_compatible / _pdbx_entry_details.has_protein_modification

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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 (5'-D(*GP*AP*GP*GP*CP*(5CM)P*GP*CP*CP*TP*GP*C)-3')
D: DNA (5'-D(*GP*CP*AP*GP*G)-R(P*(PYO))-D(P*GP*GP*CP*CP*TP*C)-3')
hetero molecules


Theoretical massNumber of molelcules
Total (without water)107,00311
Polymers106,1473
Non-polymers8568
Water4,053225
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6810 Å2
ΔGint-26 kcal/mol
Surface area36830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)161.886, 77.698, 115.408
Angle α, β, γ (deg.)90.000, 125.669, 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-111-

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) / Strain (production host): BL21(DE3) / 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 (5'-D(*GP*AP*GP*GP*CP*(5CM)P*GP*CP*CP*TP*GP*C)-3')


Mass: 3678.407 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#3: DNA chain DNA (5'-D(*GP*CP*AP*GP*G)-R(P*(PYO))-D(P*GP*GP*CP*CP*TP*C)-3')


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, 233 molecules

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


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.: 4 / 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.: 225 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN
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: 2.96 Å3/Da / Density % sol: 58.43 %
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 28, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→45.21 Å / Num. obs: 55268 / % possible obs: 95.3 % / Redundancy: 4.3 % / Biso Wilson estimate: 45.6 Å2 / Rmerge(I) obs: 0.159 / Rpim(I) all: 0.076 / Net I/σ(I): 9.4
Reflection shellResolution: 2.2→2.33 Å / Rmerge(I) obs: 1.021 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 4682 / CC1/2: 0.453 / CC star: 0.789 / Rpim(I) all: 0.662 / % possible all: 81.5

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
SERGUIdata collection
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3SWR

3swr


Resolution: 2.2→45.21 Å / SU ML: 0.2583 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 27.2122
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2252 1997 3.62 %
Rwork0.1939 53115 -
obs0.195 55112 93.52 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 70.81 Å2
Refinement stepCycle: LAST / Resolution: 2.2→45.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6194 487 50 225 6956
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00436946
X-RAY DIFFRACTIONf_angle_d0.68279545
X-RAY DIFFRACTIONf_chiral_restr0.04471036
X-RAY DIFFRACTIONf_plane_restr0.00461162
X-RAY DIFFRACTIONf_dihedral_angle_d21.1822475
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.260.3827870.30432282X-RAY DIFFRACTION56.74
2.26-2.320.32421270.28163401X-RAY DIFFRACTION84.14
2.32-2.390.29521400.26933693X-RAY DIFFRACTION91.96
2.39-2.470.29741480.2613961X-RAY DIFFRACTION98.37
2.47-2.550.27521520.2444023X-RAY DIFFRACTION99.33
2.55-2.660.26371490.23633994X-RAY DIFFRACTION98.95
2.66-2.780.26441520.224010X-RAY DIFFRACTION98.77
2.78-2.920.25171490.21383972X-RAY DIFFRACTION98.45
2.92-3.110.22631500.2143994X-RAY DIFFRACTION98.25
3.11-3.350.24841420.19853775X-RAY DIFFRACTION93.48
3.35-3.680.21971470.18753948X-RAY DIFFRACTION97.29
3.68-4.210.20031520.17014048X-RAY DIFFRACTION99.69
4.21-5.310.18641510.15883987X-RAY DIFFRACTION97.34
5.31-45.210.20111510.17664027X-RAY DIFFRACTION96.22
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)
12.824728176610.8962589599941.056322723811.31340187595-0.1042252152472.494907224770.02578415249570.287309944234-0.3938103715960.04922366583820.302208677191-0.1723195496280.2941459764220.252044105204-0.2727014766770.4370118982640.130334245178-0.08050038333650.326269745202-0.1125468342530.3006219007453.02613531993.4118223125426.9068260716
25.8698241319-1.09902666986.320436928123.79716078608-2.796000226979.109563154960.172890262693-1.10075613614-0.6823239630340.5802156370540.861217487285-0.9127568770120.69098149858-0.199320036043-1.038079334331.211662814450.371279377386-0.3479013871790.902566757169-0.3673678758790.74621788252711.4994450845-7.6458730265816.6464939889
33.806294708730.656836245769-1.573458104233.47484078638-1.633328072021.299020228630.05343661160380.898975663481-0.7885659134620.05628174282750.229160154132-0.8051966913211.273752805841.38027177422-0.2888692691491.081303381660.433892744874-0.2697581545370.91340466392-0.3240368458780.65574368052911.1022024832-6.7746369357517.7442247753
46.505900460150.5853741095013.196784385562.534103267671.785113706135.410939118820.166054058466-0.184578745556-0.3497796154620.140316000135-0.1660381447430.6159335050530.456493447268-1.094459972380.03004350155210.779455440361-0.351272939947-0.1330913824220.905529106030.2547672674540.726539512855-39.6496101371-8.8240479575617.4830945965
55.5547254621-1.051997254571.200980295571.27381283440.28570253291.7664910307-0.4330091508690.4884418266371.08451547252-0.1228031337380.0780806515037-0.0209091688495-0.524699173014-0.1423223178620.319160988570.6222987366870.0777902847422-0.1241389853960.4631005829380.1574604628510.550078759474-14.17149708627.515918726614.6555524639
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 1099 through 1600 )
2X-RAY DIFFRACTION2chain 'C' and (resid 1 through 12 )
3X-RAY DIFFRACTION3chain 'D' and (resid 13 through 24 )
4X-RAY DIFFRACTION4chain 'A' and (resid 730 through 893 )
5X-RAY DIFFRACTION5chain 'A' and (resid 894 through 1098 )

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