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- PDB-6x9k: Human DNMT1(729-1600) Bound to Zebularine-Containing 12mer dsDNA ... -

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Basic information

Entry
Database: PDB / ID: 6x9k
TitleHuman DNMT1(729-1600) Bound to Zebularine-Containing 12mer dsDNA and Inhibitor GSK3685032A
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/TRANSFERASE INHIBITOR/DNA / EPIGENETICS / DNA METHYLTRANSFERASE FOLD / MAINTENANCE METHYLATION / INHIBITION / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex / TRANSFERASE-TRANSFERASE INHIBITOR-DNA 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 / 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 / STAT3 nuclear events downstream of ALK signaling / female germ cell nucleus / methyl-CpG binding / lncRNA binding / DNA methylation-dependent constitutive heterochromatin formation / negative regulation of gene expression via chromosomal CpG island methylation / 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 / promoter-specific chromatin binding / cellular response to amino acid stimulus / 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-UXM / DNA / DNA (> 10) / DNA (cytosine-5)-methyltransferase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.65 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

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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)107,25715
Polymers106,1473
Non-polymers1,11012
Water3,405189
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6810 Å2
ΔGint4 kcal/mol
Surface area38750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)161.318, 78.336, 117.068
Angle α, β, γ (deg.)90.000, 125.761, 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-Gold(DE3)pLysS AG' (bacteria)
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 , 4 types, 201 molecules

#4: Chemical ChemComp-ZN / ZINC ION


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


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-UXM / (2R)-2-{[6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl]sulfanyl}-2-phenylacetamide


Mass: 420.531 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24N6OS / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 189 / 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: 2.83 Å3/Da / Density % sol: 56.5 %
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: Jun 10, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.65→40 Å / Num. obs: 34128 / % possible obs: 98.6 % / Redundancy: 7.9 % / Biso Wilson estimate: 54.96 Å2 / Rmerge(I) obs: 0.132 / Rpim(I) all: 0.048 / Net I/σ(I): 14.8
Reflection shellResolution: 2.65→2.74 Å / Redundancy: 4 % / Rmerge(I) obs: 0.749 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 3087 / CC1/2: 0.545 / CC star: 0.84 / Rpim(I) all: 0.385 / % possible all: 90.3

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
SERGUIdata collection
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 6X9I

6x9i


Resolution: 2.65→40 Å / SU ML: 0.3213 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 23.6723
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2279 1706 5 %
Rwork0.1824 32408 -
obs0.1847 34114 98.44 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 69.79 Å2
Refinement stepCycle: LAST / Resolution: 2.65→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6511 487 68 189 7255
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0047335
X-RAY DIFFRACTIONf_angle_d0.670110064
X-RAY DIFFRACTIONf_chiral_restr0.04421080
X-RAY DIFFRACTIONf_plane_restr0.00511235
X-RAY DIFFRACTIONf_dihedral_angle_d20.18692692
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.65-2.730.33641260.2932411X-RAY DIFFRACTION88.18
2.73-2.820.29261380.26882603X-RAY DIFFRACTION96.18
2.82-2.920.26511430.25022711X-RAY DIFFRACTION99.24
2.92-3.030.34331420.24912710X-RAY DIFFRACTION99.76
3.03-3.170.29541430.23082724X-RAY DIFFRACTION99.79
3.17-3.340.24851450.20842727X-RAY DIFFRACTION99.72
3.34-3.550.25821430.1912725X-RAY DIFFRACTION99.58
3.55-3.820.23151430.18162713X-RAY DIFFRACTION99.37
3.82-4.20.20751440.1562741X-RAY DIFFRACTION100
4.2-4.810.17161450.13962756X-RAY DIFFRACTION100
4.81-6.060.19761460.15492773X-RAY DIFFRACTION99.9
6.06-400.19821480.16412814X-RAY DIFFRACTION99.53
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)
18.46358727559-1.366008602453.879716305083.21645574058-1.193930059795.51994969237-0.153390575862-0.274630647545-0.009764485196370.0922238818795-0.156302434318-0.7177516135560.05822391180250.4071772220560.2640687843440.6280218341740.172993857182-0.08612263544630.51247515861-0.05213897974350.5600307503194.94848782969-10.890903772129.3330731076
21.54584760795-0.7543275015740.6150576476519.525577965361.990145213754.305942567740.246450225866-0.2239419969650.2995182555030.0636140259918-0.207685634958-1.069749150910.1536187068020.652496934544-0.06371574820640.5461606731-0.142685536213-0.05917322452690.6928379782090.03277561451750.49631533074-2.7154138719120.770343230231.8368905792
34.568973243845.47624876812-1.012424343675.12438110395-1.011857227310.2269620580520.404488202873-1.265661265430.4057830361130.536806944365-0.2384640604370.112375827418-0.160213408313-0.0485517397599-0.151222432230.610665514358-0.148615870609-0.03263227490550.9879188334540.003247742977460.448407583089-30.566956904819.866721243941.2110377465
42.40814648813-0.6260544802520.0126998279130.8514297771990.176927566111.45804377067-0.00541604693204-0.1316006234890.0468774674034-0.04181725931670.1519376166840.0671231062640.0831300942534-0.0888801660218-0.1262645480450.422680340952-0.0491089205983-0.07819834403670.3109663924520.06806235537620.239301422854-34.77371735267.2087174904521.2395199758
51.18185669206-1.25192546043-1.268364237475.511211866133.805024235282.800214763220.3063710524721.82127977741-0.838552047157-0.828425250790.488278380930.7973834302860.0695072303280.811956379642-0.774351618520.94275819078-0.172546966687-0.3173736113471.222265860940.3288625364350.749556018034-46.4636360394-8.8731031566231.0164797171
68.312172965612.81042873109-2.81822980787.683327289163.628972941814.07135294589-0.9190525913770.538553271515-0.372467062922-1.095932905130.3824103707230.899026439173-0.21179443327-0.01006901582540.6805269905031.012086723270.0683169128789-0.2701041098221.063570960950.1337914514660.768133802289-45.8848357736-8.3275013790530.402416027
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 730 through 878 )
2X-RAY DIFFRACTION2chain 'A' and (resid 879 through 951 )
3X-RAY DIFFRACTION3chain 'A' and (resid 952 through 1013 )
4X-RAY DIFFRACTION4chain 'A' and (resid 1014 through 1600 )
5X-RAY DIFFRACTION5chain 'C' and (resid 1 through 12 )
6X-RAY DIFFRACTION6chain 'D' and (resid 13 through 24 )

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