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- PDB-5dtq: Crystal structure of Dot1L in complex with inhibitor CPD3 [(2,6-d... -

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Basic information

Entry
Database: PDB / ID: 5dtq
TitleCrystal structure of Dot1L in complex with inhibitor CPD3 [(2,6-dichlorophenyl)(quinolin-6-yl)methanone]
ComponentsHistone-lysine N-methyltransferase, H3 lysine-79 specific
KeywordsTRANSFERASE / Inhibitor / Complex / Methyltransferase
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
(2,6-dichlorophenyl)(quinolin-6-yl)methanone / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 Å
AuthorsScheufler, C. / Be, C. / Moebitz, H. / Stauffer, F.
CitationJournal: Acs Med.Chem.Lett. / Year: 2016
Title: Optimization of a Fragment-Based Screening Hit toward Potent DOT1L Inhibitors Interacting in an Induced Binding Pocket.
Authors: Scheufler, C. / Mobitz, H. / Gaul, C. / Ragot, C. / Be, C. / Fernandez, C. / Beyer, K.S. / Tiedt, R. / Stauffer, F.
History
DepositionSep 18, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jun 15, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 7, 2016Group: Database references
Revision 1.2Jan 10, 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)77,5174
Polymers76,9132
Non-polymers6042
Water4,702261
1
A: Histone-lysine N-methyltransferase, H3 lysine-79 specific
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,7592
Polymers38,4571
Non-polymers3021
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Histone-lysine N-methyltransferase, H3 lysine-79 specific
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,7592
Polymers38,4571
Non-polymers3021
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)158.651, 158.651, 74.179
Angle α, β, γ (deg.)90.00, 90.00, 120.00
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-5F6 / (2,6-dichlorophenyl)(quinolin-6-yl)methanone


Mass: 302.155 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H9Cl2NO
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 261 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.5 Å3/Da / Density % sol: 64.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 1.6M K/Na tartrate, 0.1M Hepes pH6.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99996 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 30, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99996 Å / Relative weight: 1
ReflectionResolution: 2.61→50 Å / Num. all: 32594 / Num. obs: 32584 / % possible obs: 100 % / Redundancy: 10.1 % / Biso Wilson estimate: 63.16 Å2 / Rmerge(I) obs: 0.155 / Net I/σ(I): 16.07
Reflection shellResolution: 2.61→2.68 Å / Redundancy: 10.2 % / Rmerge(I) obs: 1.287 / Mean I/σ(I) obs: 2.55 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1nw3

1nw3


Resolution: 2.61→45.8 Å / Cor.coef. Fo:Fc: 0.9321 / Cor.coef. Fo:Fc free: 0.9071 / SU R Cruickshank DPI: 0.315 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.314 / SU Rfree Blow DPI: 0.217 / SU Rfree Cruickshank DPI: 0.22
RfactorNum. reflection% reflectionSelection details
Rfree0.2079 1630 5 %RANDOM
Rwork0.173 ---
obs0.1748 32584 99.98 %-
Displacement parametersBiso mean: 55.95 Å2
Baniso -1Baniso -2Baniso -3
1-9.2235 Å20 Å20 Å2
2--9.2235 Å20 Å2
3----18.4469 Å2
Refine analyzeLuzzati coordinate error obs: 0.336 Å
Refinement stepCycle: 1 / Resolution: 2.61→45.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5088 0 40 261 5389
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015265HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.057162HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1755SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes126HARMONIC2
X-RAY DIFFRACTIONt_gen_planes760HARMONIC5
X-RAY DIFFRACTIONt_it5265HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.86
X-RAY DIFFRACTIONt_other_torsion18.1
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion677SEMIHARMONIC5
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_contact6020SEMIHARMONIC4
LS refinement shellResolution: 2.61→2.7 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.3337 150 5.01 %
Rwork0.2507 2842 -
all0.2548 2992 -
obs--99.98 %
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)
13.7718-0.73690.09841.7352-0.17310.7260.0770.37180.431-0.2917-0.01260.3045-0.1202-0.0038-0.0643-0.08090.0388-0.0336-0.10260.0377-0.1893-28.910134.0784-9.5295
23.106-0.8796-0.42422.12720.52510.4178-0.07490.0520.108-0.1373-0.04040.52020.069-0.25730.1153-0.14650.0182-0.055-0.0145-0.0128-0.1546-50.049612.37-9.5769
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* L|* }
2X-RAY DIFFRACTION2{ B|* M|* }

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