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- PDB-5dtr: Crystal structure of Dot1L in complex with inhibitor CPD5 [N-(2,6... -

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Basic information

Entry
Database: PDB / ID: 5dtr
TitleCrystal structure of Dot1L in complex with inhibitor CPD5 [N-(2,6-dichlorophenyl)-4-methoxy-N-methylquinolin-6-amine]
ComponentsHistone-lysine N-methyltransferase, H3 lysine-79 specificHistone methyltransferase
KeywordsTRANSFERASE / Inhibitor / Complex / Methyltransferase
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-5F7 / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.34 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)77,5804
Polymers76,9132
Non-polymers6662
Water5,675315
1
A: Histone-lysine N-methyltransferase, H3 lysine-79 specific
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,7902
Polymers38,4571
Non-polymers3331
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)38,7902
Polymers38,4571
Non-polymers3331
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)158.435, 158.435, 73.955
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 / Histone methyltransferase / 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-5F7 / N-(2,6-dichlorophenyl)-4-methoxy-N-methylquinolin-6-amine


Mass: 333.212 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H14Cl2N2O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 315 / 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: 3.48 Å3/Da / Density % sol: 64.69 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 1.2M 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: 0.99985 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 18, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99985 Å / Relative weight: 1
ReflectionResolution: 2.34→50 Å / Num. all: 44848 / Num. obs: 44838 / % possible obs: 100 % / Redundancy: 10.2 % / Biso Wilson estimate: 49.04 Å2 / Rmerge(I) obs: 0.087 / Net I/σ(I): 21.31
Reflection shellResolution: 2.34→2.4 Å / Redundancy: 10.3 % / Rmerge(I) obs: 0.925 / Mean I/σ(I) obs: 3.25 / % 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: 2.34→42.46 Å / Cor.coef. Fo:Fc: 0.9442 / Cor.coef. Fo:Fc free: 0.9223 / SU R Cruickshank DPI: 0.195 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.196 / SU Rfree Blow DPI: 0.17 / SU Rfree Cruickshank DPI: 0.171
RfactorNum. reflection% reflectionSelection details
Rfree0.2104 2241 5 %RANDOM
Rwork0.1727 ---
obs0.1746 44836 100 %-
Displacement parametersBiso mean: 56.64 Å2
Baniso -1Baniso -2Baniso -3
1-7.5314 Å20 Å20 Å2
2--7.5314 Å20 Å2
3----15.0628 Å2
Refine analyzeLuzzati coordinate error obs: 0.305 Å
Refinement stepCycle: 1 / Resolution: 2.34→42.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5071 0 44 315 5430
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015250HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.027140HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1755SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes128HARMONIC2
X-RAY DIFFRACTIONt_gen_planes757HARMONIC5
X-RAY DIFFRACTIONt_it5250HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.99
X-RAY DIFFRACTIONt_other_torsion16.7
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion675SEMIHARMONIC5
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_contact6105SEMIHARMONIC4
LS refinement shellResolution: 2.34→2.4 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2807 165 5 %
Rwork0.2081 3133 -
all0.2115 3298 -
obs--100 %
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)
13.059-1.32970.31512.7073-0.07970.7438-0.0524-0.3588-0.12950.29060.1178-0.5648-0.07510.1219-0.0654-0.19410-0.0416-0.11260.0097-0.096743.9491-8.06569.1461
22.8171-0.6225-0.65011.92610.15150.5349-0.0055-0.141-0.40860.0837-0.094-0.35630.20280.05930.0995-0.12460.0524-0.0253-0.15370.0631-0.054435.6766-37.19069.1603
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* L|* }
2X-RAY DIFFRACTION2{ B|* M|* }

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