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- PDB-4eki: Crystal Structure of DOT1L in complex with EPZ004777 -

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Basic information

Entry
Database: PDB / ID: 4eki
TitleCrystal Structure of DOT1L in complex with EPZ004777
ComponentsHistone-lysine N-methyltransferase, H3 lysine-79 specificHistone methyltransferase
Keywordstransferase/transferase inhibitor / methyltransferase / transferase-transferase inhibitor complex
Function / homology
Function and homology information


histone H3K79 trimethyltransferase activity / [histone H3]-lysine79 N-trimethyltransferase / histone H3K79 methyltransferase activity / regulation of transcription regulatory region DNA binding / histone H3 methyltransferase activity / regulation of receptor signaling pathway via JAK-STAT / histone methyltransferase activity / heterochromatin formation / telomere organization / DNA damage checkpoint signaling ...histone H3K79 trimethyltransferase activity / [histone H3]-lysine79 N-trimethyltransferase / histone H3K79 methyltransferase activity / regulation of transcription regulatory region DNA binding / histone H3 methyltransferase activity / regulation of receptor signaling pathway via JAK-STAT / histone methyltransferase activity / heterochromatin formation / telomere organization / DNA damage checkpoint signaling / PKMTs methylate histone lysines / gene expression / methylation / RNA polymerase II-specific DNA-binding transcription factor binding / nucleic acid binding / transcription coactivator activity / intracellular membrane-bounded organelle / DNA repair / positive regulation of cell population proliferation / 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 / PHASER / Resolution: 2.85 Å
AuthorsJin, L.
CitationJournal: Chem.Biol.Drug Des. / Year: 2012
Title: Conformational adaptation drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L.
Authors: Basavapathruni, A. / Jin, L. / Daigle, S.R. / Majer, C.R. / Therkelsen, C.A. / Wigle, T.J. / Kuntz, K.W. / Chesworth, R. / Pollock, R.M. / Scott, M.P. / Moyer, M.P. / Richon, V.M. / Copeland, R.A. / Olhava, E.J.
History
DepositionApr 9, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 17, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 9, 2013Group: 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_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)49,3945
Polymers48,5661
Non-polymers8284
Water18010
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)155.053, 155.053, 48.452
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 / Histone methyltransferase / 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-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 / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 10 / 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: 3.46 Å3/Da / Density % sol: 64.47 %
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, pH 5.2, compound soaked into cross-linked DOT1L-SAM crystal, temperature 293K, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 2, 2010
RadiationMonochromator: SI 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.85→50 Å / Num. obs: 15834 / % possible obs: 99.8 % / Observed criterion σ(I): 1 / Redundancy: 5.6 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 23.1
Reflection shellResolution: 2.85→2.95 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.539 / Mean I/σ(I) obs: 4 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
REFMAC5.6.0117refinement
HKL-2000data reduction
HKL-3000data scaling
RefinementMethod to determine structure: PHASER
Starting model: PDB ENTRY 3QOW

3qow


Resolution: 2.85→41.09 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.925 / SU B: 12.475 / SU ML: 0.244 / Cross valid method: THROUGHOUT / ESU R: 0.471 / ESU R Free: 0.319 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.26196 785 5 %RANDOM
Rwork0.20934 ---
obs0.21209 15029 99.64 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 90.38 Å2
Baniso -1Baniso -2Baniso -3
1-0.37 Å20.19 Å20 Å2
2--0.37 Å20 Å2
3----0.56 Å2
Refinement stepCycle: LAST / Resolution: 2.85→41.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2591 0 54 10 2655
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.022709
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4561.9723674
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4275316
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.64923.953129
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.46615465
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.6731517
X-RAY DIFFRACTIONr_chiral_restr0.1040.2396
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0212042
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: 2.849→2.923 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.406 61 -
Rwork0.27 974 -
obs--98.1 %

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