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- PDB-6te6: Crystal structure of Dot1L in complex with an inhibitor (compound 3). -

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Basic information

Entry
Database: PDB / ID: 6te6
TitleCrystal structure of Dot1L in complex with an inhibitor (compound 3).
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-N4W / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.98 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 11, 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 1.2Mar 11, 2020Group: Data collection / Category: reflns_shell / Item: _reflns_shell.percent_possible_all
Revision 1.3Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)77,8454
Polymers76,9132
Non-polymers9322
Water7,710428
1
A: Histone-lysine N-methyltransferase, H3 lysine-79 specific
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,9232
Polymers38,4571
Non-polymers4661
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)38,9232
Polymers38,4571
Non-polymers4661
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)158.540, 158.540, 74.230
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) / Gene: DOT1L, KIAA1814, KMT4 / Production host: Escherichia coli (E. coli)
References: UniProt: Q8TEK3, histone-lysine N-methyltransferase
#2: Chemical ChemComp-N4W / ~{N}1-[(~{S})-(3-chlorophenyl)-pyridin-2-yl-methyl]-4-methylsulfonyl-~{N}2-pyrimidin-2-yl-benzene-1,2-diamine


Mass: 465.955 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H20ClN5O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 428 / 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: 3.5 Å3/Da / Density % sol: 64.87 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 1.28 M Na/K-tartrate 0.1 M Hepes pH 6.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99999 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Dec 8, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 1.98→45.77 Å / Num. obs: 74086 / % possible obs: 99.9 % / Redundancy: 10.203 % / Biso Wilson estimate: 37.94 Å2 / Rmerge F obs: 0.09 / Rmerge(I) obs: 0.063 / Rrim(I) all: 0.066 / Χ2: 1.015 / Net I/σ(I): 22.94 / Num. measured all: 755867 / Scaling rejects: 43
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
1.98-2.0310.0080.7871.0472.3754356545954311.10499.5
2.03-2.0910.3180.5670.8443.0955035533553340.889100
2.09-2.1510.1910.4220.617452371514051390.65100
2.15-2.219.6770.3390.4675.1248638502750260.493100
2.21-2.299.90.2650.3716.5448092485848580.391100
2.29-2.3710.6240.2010.2968.1950391474347430.312100
2.37-2.4610.6160.160.2379.9848154453845360.249100
2.46-2.5610.5650.1210.18312.6446453439843970.192100
2.56-2.6710.3950.0960.15215.0143461418141810.16100
2.67-2.89.9860.0720.11419.0740043401040100.12100
2.8-2.959.7890.0560.08724.0737560383738370.092100
2.95-3.1310.6590.0380.06731.5838853364636450.071100
3.13-3.3510.6620.030.05339.2936175339333930.056100
3.35-3.6110.3990.020.04149.8233224319631950.044100
3.61-3.969.9410.0170.03556.3229048292429220.03799.9
3.96-4.439.2940.0140.02962.6524628264826500.031100
4.43-5.1110.5340.0110.02772.4124775235223520.028100
5.11-6.2610.3750.0120.02767.0820844200920090.029100
6.26-8.859.4640.0120.02468.1814669155115500.02599.9
8.85-45.7710.3610.0080.01981.7590978868780.0299.1

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Processing

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

5drt


Resolution: 1.98→45.77 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.947 / SU R Cruickshank DPI: 0.116 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.118 / SU Rfree Blow DPI: 0.11 / SU Rfree Cruickshank DPI: 0.109
RfactorNum. reflection% reflectionSelection details
Rfree0.201 3704 5 %RANDOM
Rwork0.178 ---
obs0.179 74074 99.9 %-
Displacement parametersBiso max: 224.08 Å2 / Biso mean: 51.79 Å2 / Biso min: 23.04 Å2
Baniso -1Baniso -2Baniso -3
1-5.5458 Å20 Å20 Å2
2--5.5458 Å20 Å2
3----11.0916 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: final / Resolution: 1.98→45.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5131 0 64 428 5623
Biso mean--38.4 55.16 -
Num. residues----642
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1789SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes899HARMONIC5
X-RAY DIFFRACTIONt_it5335HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion682SEMIHARMONIC5
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_contact6333SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5335HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg7258HARMONIC20.93
X-RAY DIFFRACTIONt_omega_torsion2.97
X-RAY DIFFRACTIONt_other_torsion16.41
LS refinement shellResolution: 1.98→1.99 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2512 74 4.99 %
Rwork0.2476 1408 -
all0.2478 1482 -
obs--97.28 %
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)
12.2879-1.03230.36592.4214-0.20070.7469-0.033-0.2857-0.01330.32110.0568-0.5309-0.07560.1147-0.0238-0.1709-0.0061-0.0559-0.11390.0077-0.084844.0193-8.06228.5926
22.521-0.4267-0.48561.50170.10180.4958-0.0231-0.0892-0.38360.0983-0.0709-0.2590.22240.04810.094-0.11450.048-0.0249-0.15750.0445-0.050335.7395-37.0688.4055
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 - 331
4X-RAY DIFFRACTION2{ B|* M|* }M1

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