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- PDB-4er3: Crystal Structure of Human DOT1L in complex with inhibitor EPZ004777 -

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Basic information

Entry
Database: PDB / ID: 4er3
TitleCrystal Structure of Human DOT1L in complex with inhibitor EPZ004777
ComponentsHistone-lysine N-methyltransferase, H3 lysine-79 specific
KeywordsTransferase/Transferase Inhibitor / histone / methyltransferase / epigenetics / Transferase-Transferase Inhibitor complex / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


[histone H3]-lysine79 N-trimethyltransferase / histone H3K79 methyltransferase activity / histone H3K79 trimethyltransferase activity / regulation of transcription regulatory region DNA binding / regulation of receptor signaling pathway via JAK-STAT / histone H3 methyltransferase activity / histone methyltransferase activity / subtelomeric heterochromatin formation / telomere organization / DNA damage checkpoint signaling ...[histone H3]-lysine79 N-trimethyltransferase / histone H3K79 methyltransferase activity / histone H3K79 trimethyltransferase activity / regulation of transcription regulatory region DNA binding / regulation of receptor signaling pathway via JAK-STAT / histone H3 methyltransferase activity / histone methyltransferase activity / subtelomeric heterochromatin formation / telomere organization / DNA damage checkpoint signaling / PKMTs methylate histone lysines / methylation / gene expression / nucleic acid binding / RNA polymerase II-specific DNA-binding transcription factor binding / transcription coactivator activity / chromosome, telomeric region / DNA repair / intracellular membrane-bounded organelle / 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-0QK / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.4 Å
AuthorsWernimont, A.K. / Tempel, W. / Yu, W. / Scopton, A. / Li, Y. / Nguyen, K.T. / Federation, A. / Marineau, J. / Qi, J. / Vedadi, M. ...Wernimont, A.K. / Tempel, W. / Yu, W. / Scopton, A. / 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 16, 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)41,95215
Polymers40,8081
Non-polymers1,14414
Water32418
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)155.705, 155.705, 48.486
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

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Protein , 1 types, 1 molecules A

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


Mass: 40808.277 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

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Non-polymers , 5 types, 32 molecules

#2: Chemical ChemComp-0QK / 7-{5-[(3-{[(4-tert-butylphenyl)carbamoyl]amino}propyl)(propan-2-yl)amino]-5-deoxy-beta-D-ribofuranosyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine


Mass: 539.670 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H41N7O4
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-UNX / UNKNOWN ATOM OR ION


Num. of mol.: 6 / Source method: obtained synthetically
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 18 / 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: 4.16 Å3/Da / Density % sol: 70.42 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 1.6M (NH4)2SO4, 0.01M MgCl2, 0.1M NaCaCo, pH 5.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97931 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 29, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 2.4→47.859 Å / Num. all: 26567 / Num. obs: 26567 / % possible obs: 99.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 11 % / Rsym value: 0.106 / Net I/σ(I): 12.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2.4-2.5310.60.71534082938470.715100
2.53-2.6810.90.4634.43973136610.463100
2.68-2.8711.10.3046.33811834330.304100
2.87-3.111.20.1889.43580931930.188100
3.1-3.3911.20.11614.33329529700.116100
3.39-3.7911.20.08719.12996726770.087100
3.79-4.3811.20.09722.82656223720.097100
4.38-5.3711.10.10425.22250220260.104100
5.37-7.59110.07524.11729515750.075100
7.59-45.6269.50.05425.576838130.05490.2

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.3.16data scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
31IDdata collection
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.4→35 Å / Cor.coef. Fo:Fc: 0.925 / Cor.coef. Fo:Fc free: 0.9 / WRfactor Rfree: 0.2917 / WRfactor Rwork: 0.2582 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.7848 / SU B: 7.761 / SU ML: 0.181 / SU R Cruickshank DPI: 0.2528 / SU Rfree: 0.2195 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.253 / ESU R Free: 0.22 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2819 1310 4.9 %RANDOM
Rwork0.2503 ---
all0.2519 26637 --
obs0.2519 26518 99.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 115.91 Å2 / Biso mean: 54.199 Å2 / Biso min: 29.64 Å2
Baniso -1Baniso -2Baniso -3
1--1.59 Å2-0.79 Å20 Å2
2---1.59 Å20 Å2
3---2.38 Å2
Refinement stepCycle: LAST / Resolution: 2.4→35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2424 0 78 18 2520
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0212598
X-RAY DIFFRACTIONr_bond_other_d0.0010.021690
X-RAY DIFFRACTIONr_angle_refined_deg1.1541.9453543
X-RAY DIFFRACTIONr_angle_other_deg0.8822.9944123
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0835318
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.91324.174115
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.12115406
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.491513
X-RAY DIFFRACTIONr_chiral_restr0.070.2388
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212880
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02525
X-RAY DIFFRACTIONr_mcbond_it0.6861.51582
X-RAY DIFFRACTIONr_mcbond_other0.0931.5631
X-RAY DIFFRACTIONr_mcangle_it1.28122551
X-RAY DIFFRACTIONr_scbond_it1.44831016
X-RAY DIFFRACTIONr_scangle_it2.4684.5992
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.416 101 -
Rwork0.376 1825 -
all-1926 -
obs--99.9 %

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