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- PDB-6x9j: Human DNMT1(729-1600) Bound to Zebularine-Containing 12mer dsDNA ... -

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Basic information

Entry
Database: PDB / ID: 6x9j
TitleHuman DNMT1(729-1600) Bound to Zebularine-Containing 12mer dsDNA and Inhibitor GSK3830052
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


negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching / : / epigenetic programming of gene expression / cellular response to bisphenol A / negative regulation of vascular associated smooth muscle cell apoptotic process / DNA-methyltransferase activity / DNA (cytosine-5-)-methyltransferase / DNA (cytosine-5-)-methyltransferase activity / SUMOylation of DNA methylation proteins / DNA methylation-dependent heterochromatin formation ...negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching / : / epigenetic programming of gene expression / cellular response to bisphenol A / negative regulation of vascular associated smooth muscle cell apoptotic process / DNA-methyltransferase activity / DNA (cytosine-5-)-methyltransferase / DNA (cytosine-5-)-methyltransferase activity / SUMOylation of DNA methylation proteins / DNA methylation-dependent heterochromatin formation / negative regulation of gene expression via chromosomal CpG island methylation / female germ cell nucleus / methyl-CpG binding / pericentric heterochromatin / positive regulation of vascular associated smooth muscle cell proliferation / DNA methylation / PRC2 methylates histones and DNA / replication fork / Defective pyroptosis / promoter-specific chromatin binding / cellular response to amino acid stimulus / NoRC negatively regulates rRNA expression / negative regulation of gene expression / DNA-templated transcription / positive regulation of gene expression / negative regulation of transcription by RNA polymerase II / DNA binding / RNA 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 methylase, C-5 cytosine-specific, active site ...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 methylase, C-5 cytosine-specific, active site / C-5 cytosine-specific DNA methylases active site. / C-5 cytosine-specific DNA methylase (Dnmt) domain profile. / CXXC zinc finger domain / Zinc finger, CXXC-type / Zinc finger CXXC-type profile. / C-5 cytosine methyltransferase / C-5 cytosine-specific DNA methylase / Bromo adjacent homology (BAH) domain superfamily / Bromo adjacent homology domain / Bromo adjacent homology (BAH) domain / BAH domain / BAH domain profile. / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
Chem-X52 / DNA / DNA (> 10) / DNA (cytosine-5)-methyltransferase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.79 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

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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)107,80623
Polymers106,1473
Non-polymers1,65920
Water7,026390
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: equilibrium centrifugation
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8670 Å2
ΔGint22 kcal/mol
Surface area38710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)160.058, 77.765, 116.720
Angle α, β, γ (deg.)90.000, 125.353, 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
11A-2154-

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)
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, 410 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 / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 17 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-X52 / N-(4-{[(3,5-dicyano-4-ethyl-6-{methyl[2-(methylamino)ethyl]amino}pyridin-2-yl)sulfanyl]methyl}phenyl)-N-methylmethanesulfonamide


Mass: 472.627 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H28N6O2S2 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 390 / 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: 55.96 %
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: 1.79→34.92 Å / Num. obs: 103653 / % possible obs: 94.5 % / Redundancy: 6.7 % / Biso Wilson estimate: 33.18 Å2 / Rmerge(I) obs: 0.089 / Rpim(I) all: 0.036 / Net I/σ(I): 19.6
Reflection shellResolution: 1.79→1.85 Å / Redundancy: 4.1 % / Rmerge(I) obs: 1.39 / Mean I/σ(I) obs: 0.9 / Num. unique obs: 7967 / CC1/2: 0.365 / CC star: 0.731 / Rpim(I) all: 0.686 / % possible all: 72.9

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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: 1.79→34.92 Å / SU ML: 0.2187 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.6981
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2286 1999 1.93 %
Rwork0.2002 101498 -
obs0.2008 103497 94.21 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 56.73 Å2
Refinement stepCycle: LAST / Resolution: 1.79→34.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6482 487 102 390 7461
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00437324
X-RAY DIFFRACTIONf_angle_d0.741610036
X-RAY DIFFRACTIONf_chiral_restr0.04721075
X-RAY DIFFRACTIONf_plane_restr0.00541230
X-RAY DIFFRACTIONf_dihedral_angle_d20.66452671
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.79-1.840.38331020.35555118X-RAY DIFFRACTION67.06
1.84-1.890.36441240.31196277X-RAY DIFFRACTION81.47
1.89-1.940.33941340.2846796X-RAY DIFFRACTION88.94
1.94-20.29521400.27047134X-RAY DIFFRACTION93.2
2-2.080.28551490.25147538X-RAY DIFFRACTION98.39
2.08-2.160.25021490.22767639X-RAY DIFFRACTION99.24
2.16-2.260.25261510.21957624X-RAY DIFFRACTION99.67
2.26-2.380.24271500.21677626X-RAY DIFFRACTION99.51
2.38-2.520.23911500.21777651X-RAY DIFFRACTION99.24
2.52-2.720.23841490.21857552X-RAY DIFFRACTION98.45
2.72-2.990.23461470.21347483X-RAY DIFFRACTION97.12
2.99-3.420.2181520.20067705X-RAY DIFFRACTION99.48
3.43-4.310.19721510.17057695X-RAY DIFFRACTION99.42
4.31-34.920.20621510.16817660X-RAY DIFFRACTION97.41
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)
14.029241724391.035732270111.035182169911.21283087363-0.2650229236071.32962636535-0.100006418283-0.7129870748281.401616301310.0725867167072-0.04516628770320.251498182733-0.2228265994370.0273300506450.06451013473980.383516971744-0.0378692249595-0.02307084370490.425150948801-0.1754832781650.553377982579-18.432965829324.305705453433.0801189264
22.46871498564-0.6540551827160.2755239058860.6427975931910.2553663484411.53810083123-0.000451816795053-0.120759678144-0.2327566238360.01744795409990.1352249985920.1398724716920.196093252995-0.174406056749-0.0509261683240.261522827542-0.0636110227757-0.03294966413760.1800304052720.08751541337790.212873952029-36.24859663242.4395222948419.8842510755
36.883747150720.266160002761-1.31745310054.21430887251-1.433097820332.495688474370.620649869353-0.723322163582-0.490544085073-1.428744934570.190592485170.6965156062741.18283856212-0.296670435236-0.4696140300751.09143009632-0.163670320442-0.3095811608880.5391416236750.3249809615730.891125131486-45.4917873541-9.2730508338530.4303767832
42.42600839413-0.9329022923621.855184306936.786336381211.870685081052.468526875480.577419974168-1.0633884101-0.0954915312152-1.37096785845-0.6825401482721.625899852511.28780329707-1.716423635060.005901669589431.30024841001-0.237919561466-0.284044843061.135683378230.0631178585871.16528734493-44.4785024713-8.3568656391729.7218957552
56.25752652945-0.7970476434413.538675809521.2694623379-0.7850408083543.56381264119-0.0139542300653-0.0285105322746-0.3770767977430.0545860107586-0.0356604555645-0.2111892524350.2341337300830.4983343133930.02309781391510.4289252620880.177743471739-0.03731723155330.479883706377-0.02229409204870.3415912195515.33101967658-11.093026897929.2613760426
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 879 through 1095 )
2X-RAY DIFFRACTION2chain 'A' and (resid 1096 through 1600 )
3X-RAY DIFFRACTION3chain 'C' and (resid 1 through 12 )
4X-RAY DIFFRACTION4chain 'D' and (resid 13 through 24 )
5X-RAY DIFFRACTION5chain 'A' and (resid 729 through 878 )

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