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- PDB-4er7: Crystal Structure of human DOT1L in complex with inhibitor SGC0947 -

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Basic information

Entry
Database: PDB / ID: 4er7
TitleCrystal Structure of human DOT1L in complex with inhibitor SGC0947
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-AW3 / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.2 Å
AuthorsWernimont, A.K. / Tempel, W. / Yu, W. / Scopton, A. / Li, Y. / Nguyen, K.T. / Vedadi, M. / Bradner, J.E. / Schapira, M. / Arrowsmith, C.H. ...Wernimont, A.K. / Tempel, W. / Yu, W. / Scopton, A. / Li, Y. / Nguyen, K.T. / 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)48,6493
Polymers47,9811
Non-polymers6692
Water1,02757
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)150.617, 150.617, 52.800
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 / 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-AW3 / 5-bromo-7-{5-[(3-{[(4-tert-butylphenyl)carbamoyl]amino}propyl)amino]-5-deoxy-beta-D-ribofuranosyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine


Mass: 576.486 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H34BrN7O4
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 57 / 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: 3.6 Å3/Da / Density % sol: 65.86 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.5
Details: 3.5 M NaFormate, 0.1 M NaAcet, 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: 31-ID / Wavelength: 0.97931 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Dec 9, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 2.2→43.233 Å / Num. all: 34959 / Num. obs: 34959 / % possible obs: 99.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 11.4 % / Rsym value: 0.116 / Net I/σ(I): 13.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2.2-2.3211.40.8350.95784550680.835100
2.32-2.4611.40.531.45489547970.53100
2.46-2.6311.50.3332.35197345390.333100
2.63-2.8411.40.2012.64825442160.201100
2.84-3.1111.50.126.14453438870.12100
3.11-3.4811.50.0817.94039235270.081100
3.48-4.0211.40.0985.73560331170.098100
4.02-4.9211.40.1165.13016426560.116100
4.92-6.9611.20.096.52333820760.09100
6.96-43.2339.40.04712.51011810760.04791

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.3.16data scaling
REFMACrefinement
PDB_EXTRACT3.11data extraction
31IDdata collection
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.2→35 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.937 / WRfactor Rfree: 0.2627 / WRfactor Rwork: 0.2356 / Occupancy max: 1 / Occupancy min: 0.2 / FOM work R set: 0.8321 / SU B: 4.67 / SU ML: 0.118 / SU R Cruickshank DPI: 0.1722 / SU Rfree: 0.1561 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.172 / ESU R Free: 0.156 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2418 1722 4.9 %RANDOM
Rwork0.218 ---
all0.2192 35042 --
obs0.2192 34923 99.66 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 101.81 Å2 / Biso mean: 46.6586 Å2 / Biso min: 12.25 Å2
Baniso -1Baniso -2Baniso -3
1--0.64 Å2-0.32 Å20 Å2
2---0.64 Å20 Å2
3---0.96 Å2
Refinement stepCycle: LAST / Resolution: 2.2→35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2540 0 43 57 2640
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0222775
X-RAY DIFFRACTIONr_bond_other_d0.0030.021838
X-RAY DIFFRACTIONr_angle_refined_deg1.381.9773790
X-RAY DIFFRACTIONr_angle_other_deg0.9713.0114482
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4555341
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.69223.884121
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.1815437
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.021516
X-RAY DIFFRACTIONr_chiral_restr0.0840.2414
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213103
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02570
X-RAY DIFFRACTIONr_mcbond_it0.9261.51682
X-RAY DIFFRACTIONr_mcbond_other0.151.5668
X-RAY DIFFRACTIONr_mcangle_it1.75622723
X-RAY DIFFRACTIONr_scbond_it2.09731093
X-RAY DIFFRACTIONr_scangle_it3.4474.51067
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.393 132 -
Rwork0.331 2407 -
all-2539 -
obs--99.96 %

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