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- PDB-6tel: Crystal structure of Dot1L in complex with an inhibitor (compound 10). -

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Basic information

Entry
Database: PDB / ID: 6tel
TitleCrystal structure of Dot1L in complex with an inhibitor (compound 10).
ComponentsHistone-lysine N-methyltransferase, H3 lysine-79 specific
KeywordsTRANSFERASE / Dot1L / complex structure / inhibitor
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-N4Z / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.19 Å
AuthorsScheufler, C. / Stauffer, F. / Be, C. / Moebitz, H.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: New Potent DOT1L Inhibitors forin VivoEvaluation in Mouse.
Authors: Stauffer, F. / Weiss, A. / Scheufler, C. / Mobitz, H. / Ragot, C. / Beyer, K.S. / Calkins, K. / Guthy, D. / Kiffe, M. / Van Eerdenbrugh, B. / Tiedt, R. / Gaul, C.
History
DepositionNov 12, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 11, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 1, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Jan 24, 2024Group: 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_conn_angle / struct_conn
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_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_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
B: Histone-lysine N-methyltransferase, H3 lysine-79 specific
hetero molecules


Theoretical massNumber of molelcules
Total (without water)78,2745
Polymers76,9132
Non-polymers1,3613
Water4,306239
1
A: Histone-lysine N-methyltransferase, H3 lysine-79 specific
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,1182
Polymers38,4571
Non-polymers6611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone-lysine N-methyltransferase, H3 lysine-79 specific
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,1573
Polymers38,4571
Non-polymers7002
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)159.160, 159.160, 74.140
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number173
Space group name H-MP63

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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: 38456.594 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
References: UniProt: Q8TEK3, histone-lysine N-methyltransferase
#2: Chemical ChemComp-N4Z / ~{N}1-[(~{S})-[2,2-bis(fluoranyl)-1,3-benzodioxol-4-yl]-(3-chloranylpyridin-2-yl)methyl]-~{N}2-(4-methoxy-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-methylsulfonyl-benzene-1,2-diamine


Mass: 661.079 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H27ClF2N8O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 239 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.52 Å3/Da / Density % sol: 65.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 1.28 M K/Na tartrate 0.1 M Hepes pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00006 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Apr 26, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00006 Å / Relative weight: 1
ReflectionResolution: 2.19→42.63 Å / Num. obs: 55193 / % possible obs: 99.9 % / Redundancy: 10.264 % / Biso Wilson estimate: 44.88 Å2 / Rmerge F obs: 0.107 / Rmerge(I) obs: 0.077 / Rrim(I) all: 0.082 / Χ2: 1.008 / Net I/σ(I): 20.07 / Num. measured all: 566480 / Scaling rejects: 546
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRrim(I) all% possible all
2.19-2.2510.2921.1562.1140391.21799.3
2.25-2.3110.4861.0822.3839221.13799.4
2.31-2.3810.3520.6813.4838500.716100
2.38-2.4510.1720.5514.237400.581100
2.45-2.539.7190.4365.1836400.46100
2.53-2.6210.1940.3466.5935100.364100
2.62-2.7210.6750.2778.2733800.291100
2.72-2.8310.6270.20310.8532720.213100
2.83-2.9510.5220.15414.0631320.162100
2.95-3.110.3770.11318.3630020.119100
3.1-3.269.7470.08822.8328490.093100
3.26-3.4610.1820.06530.4827020.068100
3.46-3.710.6530.06135.0425520.064100
3.7-410.550.04642.8823580.048100
4-4.3810.2250.03850.5521940.04100
4.38-4.99.4130.03554.3719780.037100
4.9-5.6510.2740.03554.8417540.037100
5.65-6.9310.4520.03414940.035100
6.93-9.799.5440.02662.7711670.027100
9.79-42.6310.0270.02272.066580.02398.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHASERphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5DRT

5drt


Resolution: 2.19→42.63 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.948 / SU R Cruickshank DPI: 0.161 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.159 / SU Rfree Blow DPI: 0.142 / SU Rfree Cruickshank DPI: 0.144
RfactorNum. reflection% reflectionSelection details
Rfree0.212 2749 5.01 %RANDOM
Rwork0.185 ---
obs0.187 54909 99.4 %-
Displacement parametersBiso max: 190.5 Å2 / Biso mean: 63.46 Å2 / Biso min: 28.14 Å2
Baniso -1Baniso -2Baniso -3
1-4.6784 Å20 Å20 Å2
2--4.6784 Å20 Å2
3----9.3569 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 2.19→42.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4984 0 91 239 5314
Biso mean--53.27 54.77 -
Num. residues----628
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1734SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes866HARMONIC5
X-RAY DIFFRACTIONt_it5209HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion668SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact6057SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5209HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg7086HARMONIC21.01
X-RAY DIFFRACTIONt_omega_torsion2.93
X-RAY DIFFRACTIONt_other_torsion17.47
LS refinement shellResolution: 2.19→2.21 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2302 55 5 %
Rwork0.2306 1044 -
all0.2305 1099 -
obs--99.91 %
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)
13.5814-1.39160.44613.23640.03290.9223-0.0918-0.3671-0.21640.42190.1885-0.6319-0.05720.1602-0.0967-0.25130.0157-0.0469-0.20190.03110.005744.0474-7.64778.1964
22.9171-0.3166-0.63012.2748-0.06250.6581-0.0159-0.1437-0.44320.1359-0.1557-0.52530.29210.0630.1716-0.18750.0639-0.025-0.25920.07110.088335.8098-37.20338.2484
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* L|* }A5 - 332
2X-RAY DIFFRACTION1{ A|* L|* }L1
3X-RAY DIFFRACTION2{ B|* M|* }B4 - 330
4X-RAY DIFFRACTION2{ B|* M|* }M1

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