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- PDB-3sr4: Crystal Structure of Human DOT1L in Complex with a Selective Inhibitor -

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Basic information

Entry
Database: PDB / ID: 3sr4
TitleCrystal Structure of Human DOT1L in Complex with a Selective Inhibitor
ComponentsHistone-lysine N-methyltransferase, H3 lysine-79 specific
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / HDOT1 / HISTONE LYSINE METHYLTRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
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
ACETATE ION / Chem-TT8 / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsDiao, J. / Chen, P. / Yao, Y. / Prasad, B.V.V. / Song, Y.
CitationJournal: J.Am.Chem.Soc. / Year: 2011
Title: Selective Inhibitors of Histone Methyltransferase DOT1L: Design, Synthesis, and Crystallographic Studies.
Authors: Yao, Y. / Chen, P. / Diao, J. / Cheng, G. / Deng, L. / Anglin, J.L. / Prasad, B.V. / Song, Y.
History
DepositionJul 6, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 5, 2011Provider: repository / Type: Initial release
Revision 1.1Nov 16, 2011Group: Database references
Revision 1.2Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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)41,3975
Polymers40,7511
Non-polymers6464
Water1,63991
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)152.753, 152.753, 50.889
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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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: 40751.227 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN OF HDOT1L (UNP residues 1-351)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DOT1L, KIAA1814, KMT4 / Plasmid: PGEX-KG / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) RIL
References: UniProt: Q8TEK3, histone-lysine N-methyltransferase

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Non-polymers , 5 types, 95 molecules

#2: Chemical ChemComp-TT8 / (2S)-2-azanyl-4-[[(2S,3S,4R,5R)-5-[6-(methylamino)purin-9-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methylsulfanyl]butanoic acid / S-(N6-Methyladenosyl)-L-homocysteine


Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N6O5S
#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: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 91 / 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: 4.21 Å3/Da / Density % sol: 70.75 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 5.3
Details: PROTEIN SOLUTION: 20 mM Tris, pH 8.0, 200 mM NaCl, 1 mM EDTA, 10% glycerol, 3 mM inhibitor, 3 mM TCEP. RESERVOIR SOLUTION: 0.1 M HAC, pH 5.3, 1.25-1.7 M (NH4)2SO4. , VAPOR DIFFUSION, HANGING ...Details: PROTEIN SOLUTION: 20 mM Tris, pH 8.0, 200 mM NaCl, 1 mM EDTA, 10% glycerol, 3 mM inhibitor, 3 mM TCEP. RESERVOIR SOLUTION: 0.1 M HAC, pH 5.3, 1.25-1.7 M (NH4)2SO4. , VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS HTC / Detector: IMAGE PLATE / Date: Jun 7, 2011 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.5→100 Å / Num. all: 23777 / Num. obs: 23040 / % possible obs: 96.9 % / Redundancy: 12.9 % / Biso Wilson estimate: 63 Å2 / Rsym value: 0.14 / Net I/σ(I): 18
Reflection shellResolution: 2.5→2.54 Å / Redundancy: 13 % / Mean I/σ(I) obs: 3 / Num. unique all: 1232 / Rsym value: 0.863 / % possible all: 100

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Processing

Software
NameVersionClassification
StructureStudiodata collection
PHASERphasing
CNS1.3refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1NW3

1nw3


Resolution: 2.5→30.55 Å / Rfactor Rfree error: 0.008 / Data cutoff high absF: 1042822.88 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.274 1154 5 %RANDOM
Rwork0.234 ---
obs0.234 23019 96.6 %-
all-23823 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 60.7824 Å2 / ksol: 0.37 e/Å3
Displacement parametersBiso mean: 64.1 Å2
Baniso -1Baniso -2Baniso -3
1--8.77 Å20 Å20 Å2
2---8.77 Å20 Å2
3---17.54 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.39 Å0.33 Å
Luzzati d res low-5 Å
Luzzati sigma a0.33 Å0.3 Å
Refinement stepCycle: LAST / Resolution: 2.5→30.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2671 0 42 91 2804
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_dihedral_angle_d21.9
X-RAY DIFFRACTIONc_improper_angle_d0.81
X-RAY DIFFRACTIONc_mcbond_it1.621.5
X-RAY DIFFRACTIONc_mcangle_it2.822
X-RAY DIFFRACTIONc_scbond_it2.262
X-RAY DIFFRACTIONc_scangle_it3.52.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 2.5→2.54 Å / Rfactor Rfree error: 0.055 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.392 50 4.3 %
Rwork0.344 1101 -
obs-1151 95.7 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2dna-rna_rep.paramdna-rna.top
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION4ion.paramion.top
X-RAY DIFFRACTION5carbohydrate.paramcarbohydrate.top
X-RAY DIFFRACTION6TT8_par.txtTT8_top.txt
X-RAY DIFFRACTION7ACT_par.txtACT_top.txt

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