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- PDB-9hgm: Structure of human DNMT2 with bound allosteric inhibitor -

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Basic information

Entry
Database: PDB / ID: 9hgm
TitleStructure of human DNMT2 with bound allosteric inhibitor
ComponentstRNA (cytosine(38)-C(5))-methyltransferase
KeywordsTRANSFERASE / methyl transferase / tRNA methylation / allosteric inhibitor / drug design
Function / homology
Function and homology information


tRNA (cytosine38-C5)-methyltransferase / tRNA (cytidine-5-)-methyltransferase activity / tRNA stabilization / tRNA methyltransferase activity / tRNA modification in the nucleus and cytosol / tRNA modification / tRNA methylation / RNA binding / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
: / DNA methylase, C-5 cytosine-specific, conserved site / C-5 cytosine-specific DNA methylases C-terminal signature. / C-5 cytosine-specific DNA methylase (Dnmt) domain profile. / C-5 cytosine methyltransferase / C-5 cytosine-specific DNA methylase / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
: / tRNA (cytosine(38)-C(5))-methyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsSchwan, M. / Kopp, J. / Sinning, I.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)TRR319 Germany
CitationJournal: Iscience / Year: 2025
Title: DNA-encoded library screening uncovers potent DNMT2 inhibitors targeting a cryptic allosteric binding site.
Authors: Frey, A.F. / Schwan, M. / Weldert, A.C. / Kadenbach, V. / Kopp, J. / Nidoieva, Z. / Zimmermann, R.A. / Gleue, L. / Zimmer, C. / Jorg, M. / Friedland, K. / Helm, M. / Sinning, I. / Barthels, F.
History
DepositionNov 20, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 27, 2025Provider: repository / Type: Initial release
Revision 1.1Sep 10, 2025Group: Database references / Category: citation / citation_author
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_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: tRNA (cytosine(38)-C(5))-methyltransferase
B: tRNA (cytosine(38)-C(5))-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,7556
Polymers79,5362
Non-polymers1,2194
Water82946
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4020 Å2
ΔGint-10 kcal/mol
Surface area29010 Å2
Unit cell
Length a, b, c (Å)71.201, 97.345, 125.018
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein tRNA (cytosine(38)-C(5))-methyltransferase / DNA (cytosine-5)-methyltransferase-like protein 2 / Dnmt2 / DNA methyltransferase homolog HsaIIP / ...DNA (cytosine-5)-methyltransferase-like protein 2 / Dnmt2 / DNA methyltransferase homolog HsaIIP / DNA MTase homolog HsaIIP / M.HsaIIP / PuMet


Mass: 39767.887 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRDMT1, DNMT2 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: O14717, tRNA (cytosine38-C5)-methyltransferase
#2: Chemical ChemComp-A1IUL / 4-ethyl-~{N}-[[1-[[(2~{R})-1-(1~{H}-indol-3-yl)-4-[[2-(methylamino)-2-oxidanylidene-ethyl]amino]-4-oxidanylidene-butan-2-yl]carbamoyl]cyclopropyl]methyl]benzamide


Mass: 517.619 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H35N5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 46 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.72 Å3/Da / Density % sol: 54.84 %
Crystal growTemperature: 291.2 K / Method: vapor diffusion, sitting drop
Details: Crystals were grown at 291 K using sitting drop vapour diffusion. Crystallization reservoir was composed of 0.2 M magnesium chloride, 0.1 M Tris pH 8.5 and 12 % PEG8000. Crystallization ...Details: Crystals were grown at 291 K using sitting drop vapour diffusion. Crystallization reservoir was composed of 0.2 M magnesium chloride, 0.1 M Tris pH 8.5 and 12 % PEG8000. Crystallization drops contained 300 nL reservoir solution and 300 nL concentrated protein.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.8731 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Dec 3, 2023
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8731 Å / Relative weight: 1
ReflectionResolution: 2.6→48.67 Å / Num. obs: 27445 / % possible obs: 100 % / Redundancy: 9.6 % / Biso Wilson estimate: 73.17 Å2 / CC1/2: 0.999 / Rpim(I) all: 0.042 / Net I/σ(I): 10.6
Reflection shellResolution: 2.6→2.72 Å / Mean I/σ(I) obs: 1.2 / Num. unique obs: 3300 / CC1/2: 0.626 / Rpim(I) all: 0.688

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Processing

Software
NameVersionClassification
PHENIX1.21_5207refinement
XDS20230630data reduction
Aimless1.12.16data scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→48.67 Å / SU ML: 0.3703 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 28.0749
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2455 1396 5.1 %
Rwork0.1996 25969 -
obs0.2019 27365 99.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 83.24 Å2
Refinement stepCycle: LAST / Resolution: 2.6→48.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5276 0 88 46 5410
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00485476
X-RAY DIFFRACTIONf_angle_d0.58077417
X-RAY DIFFRACTIONf_chiral_restr0.0396850
X-RAY DIFFRACTIONf_plane_restr0.0037939
X-RAY DIFFRACTIONf_dihedral_angle_d14.56332067
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.690.37961320.33742535X-RAY DIFFRACTION99.63
2.69-2.80.35151420.31162562X-RAY DIFFRACTION99.96
2.8-2.930.30491310.2852562X-RAY DIFFRACTION99.89
2.93-3.080.29771300.28042576X-RAY DIFFRACTION99.82
3.08-3.280.27681490.24932561X-RAY DIFFRACTION99.85
3.28-3.530.24271570.21782555X-RAY DIFFRACTION99.96
3.53-3.880.27051370.19792597X-RAY DIFFRACTION99.96
3.88-4.440.221450.16642613X-RAY DIFFRACTION99.89
4.45-5.60.22251350.15982638X-RAY DIFFRACTION100
5.6-48.670.21911380.18422770X-RAY DIFFRACTION99.69
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)
13.88551219487-1.122407745850.7072861042333.5475998763-0.4842560499163.567970685270.1028221358930.3789866832850.181518329509-0.121246922017-0.24132604853-0.0114332439061-0.09394096352410.0891926691312-0.1069377081110.3772633172750.02691448115510.0149410862060.5034972442580.02512661119940.42483572550242.709874791765.315858140255.8175789752
21.5362055391-1.254541988830.8081845209891.75056402749-0.9022153087651.519803141640.1294557008980.875451327039-0.643381534536-0.412410872933-0.309927742383-0.02080347470770.5111213860640.579723927127-0.002625410580180.7383646065710.03518974665960.07632432116350.873936917778-0.06937537629120.73155636127152.971781658547.946007644757.006752922
34.4250763731-3.50756792034-2.702317019914.784717389390.229918825886.51187645537-0.2706241648290.678191993131-0.832926420908-0.230712098744-0.03194834544550.7724193211760.950626841266-0.139957501841-0.6715356721690.526912831070.3073596299640.00927807404160.724281234570.01116249138520.446010852465.962905764744.40719972858.2433777838
40.9576542059710.0151780913505-0.7636495397831.35343469951-0.3518250858470.3301141549090.3611682195430.8277561328670.273947679118-0.33568100089-0.627007816431-0.3413410901750.2846514525050.698203015617-4.31600895478E-50.55533497580.1986623854780.06789459269920.9793666108640.05071283715180.60698913499564.48396024749.886436451854.6365070133
56.019431964450.843498450969-8.913893832978.107594263070.5053837671591.99979593945-0.05742186014770.135432305995-0.06374652274910.111484369729-0.04794685983810.09172569866230.0171730571365-0.191610276115-0.004108131536651.445477886920.00876497543036-0.2350644729611.648976632730.3035301009711.43187776928.809816493850.875160670548.9617975591
63.04576067509-1.773826825440.3381862472032.94357165603-0.8042012146953.70149548112-0.130894415452-0.0423239864960.07234381734950.344375043747-0.078537375042-0.3112632164210.02554984096340.415149546332-0.08453322880340.567522828270.02425970061220.03574030656860.4484910816550.08410947295590.53126787994370.51911870738.804132075884.3392153527
71.89084051089-0.6028974621730.4499545201811.51890370691-0.64715098010.843058850714-0.157119975187-0.337474005178-0.2458779368760.6260349849950.1407347446720.357756980535-0.17506562705-0.025082877175.08865996076E-50.8050032189030.0231123713520.1004875874340.6367812277560.05296269481290.73579090265153.308172408448.235474580682.8820859984
82.76137733871-3.6596907709-0.2476566933216.336702560561.694302426077.651387080250.2242644232490.175573300517-0.4120532664750.759777264762-0.09683998095110.910900845112-0.0158409179146-1.1136353111-0.8903372360520.5869106713440.08822587417220.07970826627220.425060733110.1007343813950.36343994205549.271429494660.898926711781.7572279958
92.0748316296-0.7579718605840.02010426255071.066529823390.9169189616490.543302617304-0.447981611938-0.2554452458420.2578518908150.839242568740.126099112075-0.342194055978-0.35069462809-0.06818908363660.0004081529025580.8330031848350.0458658885945-0.05911475950280.5366104272770.02194116360550.59552400957654.701615322859.544915895785.3821549761
104.92303868355-1.55163420262-4.005199960420.4886502548941.269861603625.221290707390.05955413532680.0844878238357-0.07734747443790.00275123314649-0.0612456816389-0.02671707688560.05445271034070.10773851267-0.01220344694241.68334331012-0.299054868345-0.3727631571781.338964580330.6207862376641.9355293040256.853132268723.97964906891.4882268406
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 1 through 161 )AA1 - 1611 - 156
22chain 'A' and (resid 162 through 281 )AA162 - 281157 - 218
33chain 'A' and (resid 282 through 315 )AA282 - 315219 - 252
44chain 'A' and (resid 316 through 390 )AA316 - 390253 - 327
55chain 'A' and (resid 391 through 391 )AA391328
66chain 'B' and (resid 1 through 161 )BD1 - 1611 - 157
77chain 'B' and (resid 162 through 281 )BD162 - 281158 - 218
88chain 'B' and (resid 282 through 315 )BD282 - 315219 - 252
99chain 'B' and (resid 316 through 390 )BD316 - 390253 - 327
1010chain 'B' and (resid 391 through 391 )BD391328

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