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- PDB-8te3: Crystal structure of the methyltransferase domain of R882C/R676K ... -

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Basic information

Entry
Database: PDB / ID: 8te3
TitleCrystal structure of the methyltransferase domain of R882C/R676K DNMT3A homotetramer
ComponentsDNA (cytosine-5)-methyltransferase 3A
KeywordsTRANSFERASE / DNA methyltransferase
Function / homology
Function and homology information


positive regulation of cellular response to hypoxia / transposable element silencing by piRNA-mediated DNA methylation / protein-cysteine methyltransferase activity / regulatory ncRNA-mediated heterochromatin formation / unmethylated CpG binding / cellular response to bisphenol A / DNA (cytosine-5-)-methyltransferase / DNA (cytosine-5-)-methyltransferase activity / autosome genomic imprinting / SUMOylation of DNA methylation proteins ...positive regulation of cellular response to hypoxia / transposable element silencing by piRNA-mediated DNA methylation / protein-cysteine methyltransferase activity / regulatory ncRNA-mediated heterochromatin formation / unmethylated CpG binding / cellular response to bisphenol A / DNA (cytosine-5-)-methyltransferase / DNA (cytosine-5-)-methyltransferase activity / autosome genomic imprinting / SUMOylation of DNA methylation proteins / XY body / response to vitamin A / DNA methylation-dependent constitutive heterochromatin formation / response to ionizing radiation / negative regulation of gene expression via chromosomal CpG island methylation / hepatocyte apoptotic process / lncRNA binding / cellular response to ethanol / chromosome, centromeric region / catalytic complex / heterochromatin / Transferases; Transferring one-carbon groups; Methyltransferases / DNA methylation / PRC2 methylates histones and DNA / post-embryonic development / Defective pyroptosis / response to cocaine / cellular response to amino acid stimulus / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / euchromatin / response to lead ion / response to toxic substance / RMTs methylate histone arginines / nuclear matrix / neuron differentiation / transcription corepressor activity / response to estradiol / spermatogenesis / methylation / cellular response to hypoxia / RNA polymerase II-specific DNA-binding transcription factor binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / response to xenobiotic stimulus / negative regulation of DNA-templated transcription / chromatin binding / negative regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / identical protein binding / nucleus / cytoplasm
Similarity search - Function
DNA (cytosine-5)-methyltransferase 3A, ADD domain / : / DNA (cytosine-5-)-methyltransferase, N-terminal / DNMT3, cysteine rich ADD domain / : / DNMT3, cysteine rich ADD domain, GATA1-like zinc finger / DNMT3, ADD PHD zinc finger / ADD domain / ADD domain profile. / DNA methylase, C-5 cytosine-specific, active site ...DNA (cytosine-5)-methyltransferase 3A, ADD domain / : / DNA (cytosine-5-)-methyltransferase, N-terminal / DNMT3, cysteine rich ADD domain / : / DNMT3, cysteine rich ADD domain, GATA1-like zinc finger / DNMT3, ADD PHD zinc finger / ADD domain / ADD domain 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 / domain with conserved PWWP motif / PWWP domain / PWWP domain profile. / PWWP domain / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
S-ADENOSYL-L-HOMOCYSTEINE / DNA (cytosine-5)-methyltransferase 3A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsLu, J.W. / Song, J.K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Nat Commun / Year: 2024
Title: Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations.
Authors: Lu, J. / Guo, Y. / Yin, J. / Chen, J. / Wang, Y. / Wang, G.G. / Song, J.
History
DepositionJul 5, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 25, 2024Group: Data collection / Database references / Category: chem_comp / citation / citation_author
Item: _chem_comp.mon_nstd_flag / _chem_comp.type ..._chem_comp.mon_nstd_flag / _chem_comp.type / _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

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Assembly

Deposited unit
A: DNA (cytosine-5)-methyltransferase 3A
B: DNA (cytosine-5)-methyltransferase 3A
C: DNA (cytosine-5)-methyltransferase 3A
E: DNA (cytosine-5)-methyltransferase 3A
H: DNA (cytosine-5)-methyltransferase 3A
F: DNA (cytosine-5)-methyltransferase 3A
D: DNA (cytosine-5)-methyltransferase 3A
G: DNA (cytosine-5)-methyltransferase 3A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)263,76012
Polymers262,2228
Non-polymers1,5384
Water00
1
A: DNA (cytosine-5)-methyltransferase 3A
B: DNA (cytosine-5)-methyltransferase 3A
E: DNA (cytosine-5)-methyltransferase 3A
F: DNA (cytosine-5)-methyltransferase 3A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)131,8806
Polymers131,1114
Non-polymers7692
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: DNA (cytosine-5)-methyltransferase 3A
H: DNA (cytosine-5)-methyltransferase 3A
D: DNA (cytosine-5)-methyltransferase 3A
G: DNA (cytosine-5)-methyltransferase 3A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)131,8806
Polymers131,1114
Non-polymers7692
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)177.298, 177.298, 110.736
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number143
Space group name H-MP3

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Components

#1: Protein
DNA (cytosine-5)-methyltransferase 3A / Dnmt3a / Cysteine methyltransferase DNMT3A / DNA methyltransferase HsaIIIA / DNA MTase HsaIIIA / M.HsaIIIA


Mass: 32777.773 Da / Num. of mol.: 8 / Fragment: methyltransferase domain (UNP residues 628-912) / Mutation: R882C,R676K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DNMT3A / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q9Y6K1, DNA (cytosine-5-)-methyltransferase, Transferases; Transferring one-carbon groups; Methyltransferases
#2: Chemical
ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


Mass: 384.411 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H20N6O5S / Feature type: SUBJECT OF INVESTIGATION
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: 3.83 Å3/Da / Density % sol: 67.9 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 0.2-0.4 M potassium sodium tartrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.97648 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 21, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97648 Å / Relative weight: 1
ReflectionResolution: 3.2→50 Å / Num. obs: 64344 / % possible obs: 100 % / Redundancy: 4.3 % / Biso Wilson estimate: 63.07 Å2 / Rmerge(I) obs: 0.292 / Rpim(I) all: 0.161 / Rrim(I) all: 0.334 / Χ2: 0.674 / Net I/σ(I): 2.5 / Num. measured all: 273938
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2
3.2-3.314.21.28564310.3170.7121.4710.497
3.31-3.454.20.94564330.4860.5231.0820.541
3.45-3.64.20.66764490.6590.3690.7640.577
3.6-3.794.20.51164600.7640.2830.5860.64
3.79-4.034.20.40164210.8590.2220.4590.621
4.03-4.344.30.2864240.9280.1540.320.67
4.34-4.784.30.21364310.9560.1170.2430.761
4.78-5.474.30.21564310.9570.1180.2460.819
5.47-6.894.20.21164160.9560.1170.2410.779
6.89-504.30.06664480.9970.0360.0760.832

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data scaling
PDB_EXTRACT3.27data extraction
HKL-3000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 5YX2

5yx2


Resolution: 3.2→46.96 Å / SU ML: 0.43 / Cross valid method: THROUGHOUT / σ(F): 1.98 / Phase error: 25.8 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2413 2007 3.16 %
Rwork0.2073 61595 -
obs0.2083 63602 98.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 179.67 Å2 / Biso mean: 56.5082 Å2 / Biso min: 17.22 Å2
Refinement stepCycle: final / Resolution: 3.2→46.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13889 0 104 0 13993
Biso mean--45.8 --
Num. residues----1753
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.2-3.280.39421490.32164370451998
3.28-3.370.28761430.28524351449498
3.37-3.470.31041410.27474367450898
3.47-3.580.28161420.24144363450598
3.58-3.710.27531440.23044420456499
3.71-3.850.26291380.2164414455299
3.85-4.030.28261510.20964415456699
4.03-4.240.23311430.19274381452499
4.24-4.510.20341390.16564428456799
4.51-4.850.16361330.16364411454499
4.85-5.340.17521490.176244444593100
5.34-6.110.19441320.20394430456299
6.11-7.70.26511440.20774398454299
7.7-46.960.23531590.18624403456299

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