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- PDB-4er0: Crystal Structure of human DOT1L in complex with inhibitor FED1 -

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Basic information

Entry
Database: PDB / ID: 4er0
TitleCrystal Structure of human DOT1L in complex with inhibitor FED1
ComponentsHistone-lysine N-methyltransferase, H3 lysine-79 specificHistone methyltransferase
KeywordsTransferase/Transferase Inhibitor / histone / methyltransferase / epigenetics / Transferase-Transferase Inhibitor complex / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


histone H3K79 trimethyltransferase activity / [histone H3]-lysine79 N-trimethyltransferase / histone H3K79 methyltransferase activity / regulation of transcription regulatory region DNA binding / histone H3 methyltransferase activity / regulation of receptor signaling pathway via JAK-STAT / histone methyltransferase activity / heterochromatin formation / telomere organization / DNA damage checkpoint signaling ...histone H3K79 trimethyltransferase activity / [histone H3]-lysine79 N-trimethyltransferase / histone H3K79 methyltransferase activity / regulation of transcription regulatory region DNA binding / histone H3 methyltransferase activity / regulation of receptor signaling pathway via JAK-STAT / histone methyltransferase activity / heterochromatin formation / telomere organization / DNA damage checkpoint signaling / PKMTs methylate histone lysines / gene expression / methylation / RNA polymerase II-specific DNA-binding transcription factor binding / nucleic acid binding / transcription coactivator activity / intracellular membrane-bounded organelle / DNA repair / positive regulation of cell population proliferation / positive regulation of transcription by RNA polymerase II / protein-containing complex / DNA binding / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
434 Repressor (Amino-terminal Domain) - #60 / Histone H3-K79 methyltransferase, metazoa / Histone-lysine N-methyltransferase DOT1 domain / Histone H3-K79 methyltransferase / Histone methylation protein DOT1 / Histone-lysine N-methyltransferase DOT1 (EC 2.1.1.43) domain profile. / 434 Repressor (Amino-terminal Domain) / Vaccinia Virus protein VP39 / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Rossmann fold ...434 Repressor (Amino-terminal Domain) - #60 / Histone H3-K79 methyltransferase, metazoa / Histone-lysine N-methyltransferase DOT1 domain / Histone H3-K79 methyltransferase / Histone methylation protein DOT1 / Histone-lysine N-methyltransferase DOT1 (EC 2.1.1.43) domain profile. / 434 Repressor (Amino-terminal Domain) / Vaccinia Virus protein VP39 / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Rossmann fold / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-AW1 / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.5 Å
AuthorsWernimont, A.K. / Tempel, W. / Yu, W. / Li, Y. / Nguyen, K.T. / Federation, A. / Marineau, J. / Qi, J. / Vedadi, M. / Bradner, J.E. ...Wernimont, A.K. / Tempel, W. / Yu, W. / Li, Y. / Nguyen, K.T. / Federation, A. / Marineau, J. / Qi, J. / Vedadi, M. / Bradner, J.E. / Schapira, M. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Brown, P.J. / Structural Genomics Consortium (SGC)
CitationJournal: Nat Commun / Year: 2012
Title: Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors.
Authors: Yu, W. / Chory, E.J. / Wernimont, A.K. / Tempel, W. / Scopton, A. / Federation, A. / Marineau, J.J. / Qi, J. / Barsyte-Lovejoy, D. / Yi, J. / Marcellus, R. / Iacob, R.E. / Engen, J.R. / ...Authors: Yu, W. / Chory, E.J. / Wernimont, A.K. / Tempel, W. / Scopton, A. / Federation, A. / Marineau, J.J. / Qi, J. / Barsyte-Lovejoy, D. / Yi, J. / Marcellus, R. / Iacob, R.E. / Engen, J.R. / Griffin, C. / Aman, A. / Wienholds, E. / Li, F. / Pineda, J. / Estiu, G. / Shatseva, T. / Hajian, T. / Al-Awar, R. / Dick, J.E. / Vedadi, M. / Brown, P.J. / Arrowsmith, C.H. / Bradner, J.E. / Schapira, M.
History
DepositionApr 19, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 2, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2017Group: Refinement description / Category: software
Revision 1.2May 16, 2018Group: Data collection / 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
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone-lysine N-methyltransferase, H3 lysine-79 specific
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,5215
Polymers47,9811
Non-polymers5414
Water1086
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)150.590, 150.590, 52.878
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number170
Space group name H-MP65
DetailsAUTHORS STATE THAT THE BIOLOGICAL MOLECULE IS UNKNOWN.

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Components

#1: Protein Histone-lysine N-methyltransferase, H3 lysine-79 specific / Histone methyltransferase / DOT1-like protein / Histone H3-K79 methyltransferase / H3-K79-HMTase / Lysine N-methyltransferase 4


Mass: 47980.688 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DOT1L, KIAA1814, KMT4 / Plasmid: pET28-MHL / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 V2r Prare2
References: UniProt: Q8TEK3, histone-lysine N-methyltransferase
#2: Chemical ChemComp-AW1 / 5'-[(3-{[(4-tert-butylphenyl)carbamoyl]amino}propyl)(propan-2-yl)amino]-5'-deoxyadenosine


Mass: 540.658 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H40N8O4
#3: Chemical ChemComp-UNX / UNKNOWN ATOM OR ION


Num. of mol.: 3 / Source method: obtained synthetically
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: H2O

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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: 3.61 Å3/Da / Density % sol: 65.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.5
Details: 3.5 M NaFormate, 0.1 M NaAcet, 0.5 mM inhibitor in H2O, pH 4.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97907 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 30, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97907 Å / Relative weight: 1
ReflectionResolution: 2.5→40 Å / Num. all: 24065 / Num. obs: 24065 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 11.1 % / Biso Wilson estimate: 63 Å2 / Rmerge(I) obs: 0.07 / Χ2: 0.74 / Net I/σ(I): 7.2
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allΧ2
2.5-2.54110.8252.3511950.594
2.54-2.5911.10.7211780.609
2.59-2.6411.10.61712120.603
2.64-2.6911.10.50511780.607
2.69-2.7511.20.42411950.588
2.75-2.8211.20.38311820.605
2.82-2.8911.20.29312010.627
2.89-2.9611.20.24612050.638
2.96-3.0511.30.19411790.642
3.05-3.1511.20.14811960.655
3.15-3.2611.30.10911950.641
3.26-3.3911.30.08312080.653
3.39-3.5511.20.07212080.694
3.55-3.7311.10.06711890.802
3.73-3.9711.10.06112101.006
3.97-4.27110.05711951.192
4.27-4.710.90.05112201.291
4.7-5.3810.60.04112160.879
5.38-6.7810.70.03712250.72
6.78-4010.30.02712780.762

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.5→35 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.908 / WRfactor Rfree: 0.2672 / WRfactor Rwork: 0.2286 / Occupancy max: 1 / Occupancy min: 0.3 / FOM work R set: 0.8027 / SU B: 7.553 / SU ML: 0.172 / SU R Cruickshank DPI: 0.2661 / SU Rfree: 0.2289 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.266 / ESU R Free: 0.229 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2718 1189 5 %RANDOM
Rwork0.2367 ---
all0.2385 24048 --
obs0.2385 23979 99.83 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 89.83 Å2 / Biso mean: 52.6636 Å2 / Biso min: 26.85 Å2
Baniso -1Baniso -2Baniso -3
1--2.23 Å2-1.12 Å20 Å2
2---2.23 Å20 Å2
3---3.35 Å2
Refinement stepCycle: LAST / Resolution: 2.5→35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2425 0 42 6 2473
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0212558
X-RAY DIFFRACTIONr_bond_other_d0.0040.021666
X-RAY DIFFRACTIONr_angle_refined_deg1.021.963492
X-RAY DIFFRACTIONr_angle_other_deg0.7473.0064069
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8585320
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.99324.234111
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.46715393
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.051512
X-RAY DIFFRACTIONr_chiral_restr0.0710.2389
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212868
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02515
X-RAY DIFFRACTIONr_mcbond_it0.971.51594
X-RAY DIFFRACTIONr_mcbond_other0.1611.5635
X-RAY DIFFRACTIONr_mcangle_it1.81522567
X-RAY DIFFRACTIONr_scbond_it2.2053964
X-RAY DIFFRACTIONr_scangle_it3.634.5924
LS refinement shellResolution: 2.5→2.565 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.387 92 -
Rwork0.321 1655 -
all-1747 -
obs--99.66 %

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