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- PDB-4hra: Crystal Structure of DOT1L in Complex with EPZ-5676 -

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Basic information

Entry
Database: PDB / ID: 4hra
TitleCrystal Structure of DOT1L in Complex with EPZ-5676
ComponentsHistone-lysine N-methyltransferase, H3 lysine-79 specific
KeywordsTransferase/Transferase Inhibitor / Histone Lysine Methyltransferase / Transferase / 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
Chem-EP6 / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.15 Å
AuthorsJin, L.
CitationJournal: Blood / Year: 2013
Title: Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.
Authors: Daigle, S.R. / Olhava, E.J. / Therkelsen, C.A. / Basavapathruni, A. / Jin, L. / Boriack-Sjodin, P.A. / Allain, C.J. / Klaus, C.R. / Raimondi, A. / Scott, M.P. / Waters, N.J. / Chesworth, R. ...Authors: Daigle, S.R. / Olhava, E.J. / Therkelsen, C.A. / Basavapathruni, A. / Jin, L. / Boriack-Sjodin, P.A. / Allain, C.J. / Klaus, C.R. / Raimondi, A. / Scott, M.P. / Waters, N.J. / Chesworth, R. / Moyer, M.P. / Copeland, R.A. / Richon, V.M. / Pollock, R.M.
History
DepositionOct 26, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 31, 2013Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2013Group: Database references
Revision 1.2Sep 20, 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_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

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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)49,3214
Polymers48,5661
Non-polymers7553
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)154.430, 154.430, 47.520
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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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: 48566.234 Da / Num. of mol.: 1 / Fragment: UNP residues 1-416
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DOT1L, KIAA1814, KMT4 / Production host: Escherichia coli (E. coli)
References: UniProt: Q8TEK3, histone-lysine N-methyltransferase
#2: Chemical ChemComp-EP6 / 5'-[{cis-3-[2-(5-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl}(propan-2-yl)amino]-5'-deoxyadenosine


Mass: 562.706 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H42N8O3
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4

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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: 3.37 Å3/Da / Density % sol: 63.48 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.2
Details: 100 MM SODIUM ACETATE, 1.8-2.0 M AMMONIUM SULFATE, 5 MM TCEP, SOAKING THE COMPOUND INTO CROSS-LINKED DOT1L-SAM CRYSTAL, pH 5.2, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 1.07812 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Oct 22, 2010
RadiationMonochromator: C(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07812 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.618
11K, H, -L20.382
ReflectionResolution: 3.15→40.47 Å / Num. all: 11501 / Num. obs: 11490 / % possible obs: 99.9 % / Observed criterion σ(I): 1 / Redundancy: 9 % / Rmerge(I) obs: 0.077 / Net I/σ(I): 17.4
Reflection shellResolution: 3.15→3.23 Å / Redundancy: 9 % / Rmerge(I) obs: 0.763 / Mean I/σ(I) obs: 2.8 / Num. unique all: 838 / % possible all: 99.9

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
REFMAC5.7.0032refinement
MOSFLMdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3QOW

3qow


Resolution: 3.15→40.47 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.9 / SU B: 22.837 / SU ML: 0.415 / Cross valid method: THROUGHOUT / ESU R: 0.465 / ESU R Free: 0.086 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2557 674 5.9 %RANDOM
Rwork0.18266 ---
obs0.18658 10813 99.96 %-
all-10817 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 121.57 Å2
Baniso -1Baniso -2Baniso -3
1--57.61 Å20 Å20 Å2
2---57.61 Å20 Å2
3---115.22 Å2
Refinement stepCycle: LAST / Resolution: 3.15→40.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2605 0 51 0 2656
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0192722
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0441.9793693
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0275317
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.62224.031129
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.83215475
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2861517
X-RAY DIFFRACTIONr_chiral_restr0.070.2401
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212041
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.15→3.231 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.437 67 -
Rwork0.291 764 -
obs-831 99.64 %

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