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- PDB-4er6: Crystal structure of human DOT1L in complex with inhibitor SGC0946 -

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Basic information

Entry
Database: PDB / ID: 4er6
TitleCrystal structure of human DOT1L in complex with inhibitor SGC0946
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 / telomere organization / DNA damage checkpoint signaling / heterochromatin formation ...[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 / telomere organization / DNA damage checkpoint signaling / heterochromatin formation / PKMTs methylate histone lysines / gene expression / RNA polymerase II-specific DNA-binding transcription factor binding / methylation / nucleic acid binding / transcription coactivator activity / intracellular membrane-bounded organelle / DNA repair / 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-AW2 / BROMIDE ION / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.3 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 / pdbx_struct_conn_angle / struct_conn / 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 / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _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

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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)47,7724
Polymers47,0511
Non-polymers7213
Water45025
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)149.907, 149.907, 52.839
Angle α, β, γ (deg.)90.00, 90.00, 120.00
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: 47050.539 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-BR / BROMIDE ION


Mass: 79.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Br
#3: Chemical ChemComp-AW2 / 5-bromo-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: 618.566 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H40BrN7O4
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 25 / 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: 3.64 Å3/Da / Density % sol: 66.23 %
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: Nov 22, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 2.3→50.148 Å / Num. all: 30402 / Num. obs: 30402 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 11.1 % / Rsym value: 0.083 / Net I/σ(I): 18.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2.3-2.4211.30.9860.84945943820.986100
2.42-2.5711.30.6821.14718141690.682100
2.57-2.7511.30.4391.74432639160.439100
2.75-2.9711.30.25334152636680.253100
2.97-3.2511.20.1365.63826134070.136100
3.25-3.64110.0789.33354630420.078100
3.64-4.210.90.05511.82956227210.055100
4.2-5.1410.80.04414.22490423090.044100
5.14-7.2710.70.04314.71935818090.043100
7.27-49.0699.50.0320.993249790.0395.5

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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: 2.3→35 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.935 / WRfactor Rfree: 0.2219 / WRfactor Rwork: 0.2094 / Occupancy max: 1 / Occupancy min: 0.3 / FOM work R set: 0.8368 / SU B: 12.417 / SU ML: 0.138 / SU R Cruickshank DPI: 0.1948 / SU Rfree: 0.1642 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.195 / ESU R Free: 0.164 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.23 1479 4.9 %PDB entry 3qow
Rwork0.2162 ---
all0.2169 30436 --
obs0.2169 30370 99.78 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 111.04 Å2 / Biso mean: 58.9458 Å2 / Biso min: 34.46 Å2
Baniso -1Baniso -2Baniso -3
1--0.51 Å2-0.25 Å20 Å2
2---0.51 Å20 Å2
3---0.76 Å2
Refinement stepCycle: LAST / Resolution: 2.3→35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2600 0 42 25 2667
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0192736
X-RAY DIFFRACTIONr_angle_refined_deg1.0441.9363733
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.085340
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.64923.621116
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.33815424
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.2231515
X-RAY DIFFRACTIONr_chiral_restr0.0680.2411
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212084
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.36 85 -
Rwork0.306 2021 -
all-2106 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: 27.4566 Å / Origin y: 57.954 Å / Origin z: 3.3779 Å
111213212223313233
T0.0607 Å20.0154 Å20.0045 Å2-0.1052 Å20.0167 Å2--0.0121 Å2
L5.4689 °2-2.432 °2-0.013 °2-1.762 °20.0238 °2--0.4016 °2
S-0.0223 Å °0.193 Å °0.1269 Å °-0.033 Å °-0.0322 Å °-0.0318 Å °0.0299 Å °0.0048 Å °0.0545 Å °

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