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- PDB-4wvl: Structure-Guided DOT1L Probe Optimization by Label-Free Ligand Di... -

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Basic information

Entry
Database: PDB / ID: 4wvl
TitleStructure-Guided DOT1L Probe Optimization by Label-Free Ligand Displacement
ComponentsHistone-lysine N-methyltransferase, H3 lysine-79 specific
KeywordsTransferase/Transferase inhibitor / DOT1L / Methyltransferase / Inhibitor / Leukemia / 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-3US / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.41 Å
AuthorsXu, X. / Dhe-Paganon, S. / Blacklow, S.
CitationJournal: Acs Chem.Biol. / Year: 2015
Title: Structure-Guided DOT1L Probe Optimization by Label-Free Ligand Displacement.
Authors: Yi, J.S. / Federation, A.J. / Qi, J. / Dhe-Paganon, S. / Hadler, M. / Xu, X. / St Pierre, R. / Varca, A.C. / Wu, L. / Marineau, J.J. / Smith, W.B. / Souza, A. / Chory, E.J. / Armstrong, S.A. / Bradner, J.E.
History
DepositionNov 6, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 3, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 28, 2015Group: Database references
Revision 1.2Apr 1, 2015Group: Database references
Revision 1.3Aug 26, 2015Group: Data collection
Revision 1.4Sep 27, 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 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)41,5399
Polymers40,3191
Non-polymers1,2208
Water1,29772
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1280 Å2
ΔGint-21 kcal/mol
Surface area17480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)151.104, 151.104, 53.387
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: 40318.777 Da / Num. of mol.: 1
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

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Non-polymers , 5 types, 80 molecules

#2: Chemical ChemComp-3US / N-[4-(acetylamino)butyl]-5'-[(3-{[(4-tert-butylphenyl)carbamoyl]amino}propyl)(propan-2-yl)amino]-5'-deoxyadenosine


Mass: 653.815 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H51N9O5
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 72 / 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: 4.37 Å3/Da / Density % sol: 71.87 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 4.9
Details: A 5-fold excess of 50 mM 5-iodotubercidin (in DMSO) was mixed with protein and crystallized by using the hanging-drop vapor diffusion method at 20 degree in conditions containing 1.8 M (NH4) ...Details: A 5-fold excess of 50 mM 5-iodotubercidin (in DMSO) was mixed with protein and crystallized by using the hanging-drop vapor diffusion method at 20 degree in conditions containing 1.8 M (NH4)2SO4, 0.1 M NaAc-pH4.9. Crystals were transferred into stabilization buffer (2.5 M (NH4)2SO4, 0.1 M NaAc-pH4.9, 0.5 M NaCl), incubated with 100 uM inhibitor.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.9792 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Dec 13, 2013
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 27365 / % possible obs: 100 % / Redundancy: 7.5 % / Biso Wilson estimate: 42 Å2 / Rmerge(I) obs: 0.085 / Net I/σ(I): 26.2
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 7.6 % / Rmerge(I) obs: 0.572 / Mean I/σ(I) obs: 5 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE: 1.9_1692)refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1NW3

1nw3


Resolution: 2.41→43.62 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 20.43 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.197 1371 5.01 %Random selection
Rwork0.168 ---
obs0.169 27344 100 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 56.2 Å2
Refinement stepCycle: LAST / Resolution: 2.41→43.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2627 0 80 72 2779
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042769
X-RAY DIFFRACTIONf_angle_d0.8243751
X-RAY DIFFRACTIONf_dihedral_angle_d13.3811017
X-RAY DIFFRACTIONf_chiral_restr0.033407
X-RAY DIFFRACTIONf_plane_restr0.003475
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4058-2.49180.26831460.20442561X-RAY DIFFRACTION100
2.4918-2.59160.23991340.19652566X-RAY DIFFRACTION100
2.5916-2.70950.22611320.19432578X-RAY DIFFRACTION100
2.7095-2.85230.25281280.20082605X-RAY DIFFRACTION100
2.8523-3.0310.20871160.19632591X-RAY DIFFRACTION100
3.031-3.26490.25331380.19162576X-RAY DIFFRACTION100
3.2649-3.59330.19681410.17122602X-RAY DIFFRACTION100
3.5933-4.1130.18911500.15272603X-RAY DIFFRACTION100
4.113-5.18060.1471450.13612594X-RAY DIFFRACTION100
5.1806-43.62710.18881410.15952697X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.33451.1745-1.76732.8758-1.73124.0575-0.0569-0.1206-0.535-0.1647-0.2661-0.42310.33920.32590.21630.4905-0.01410.07870.29020.00320.516269.0888-19.5020.9176
21.7705-0.10980.46716.6621-0.71740.7498-0.06860.1408-0.1621-0.27280.02120.11050.1209-0.06310.04050.4313-0.01280.03430.2592-0.04450.279260.96562.1158-1.6104
30.7152-0.7774-0.42054.55572.03371.736-0.0331-0.04340.1213-0.12160.1229-0.0271-0.12220.0175-0.05520.36560.0470.00140.21980.0460.315363.597729.70793.2794
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN 'A' AND (RESID 4 THROUGH 90 )
2X-RAY DIFFRACTION2CHAIN 'A' AND (RESID 91 THROUGH 225 )
3X-RAY DIFFRACTION3CHAIN 'A' AND (RESID 226 THROUGH 347 )

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