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- PDB-5dsx: Crystal structure of Dot1L in complex with inhibitor CPD10 [6'-ch... -

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Entry
Database: PDB / ID: 5dsx
TitleCrystal structure of Dot1L in complex with inhibitor CPD10 [6'-chloro-1,4-dimethyl-5'-(2-methyl-6-((4-(methylamino)pyrimidin-2-yl)amino)-1H-indol-1-yl)-[3,3'-bipyridin]-2(1H)-one]
ComponentsHistone-lysine N-methyltransferase, H3 lysine-79 specific
KeywordsTRANSFERASE / Inhibitor / Complex
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
Chem-5EW / : / 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
AuthorsScheufler, C. / Gaul, C. / Be, C. / Moebitz, H.
CitationJournal: Acs Med.Chem.Lett. / Year: 2016
Title: Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach.
Authors: Chen, C. / Zhu, H. / Stauffer, F. / Caravatti, G. / Vollmer, S. / Machauer, R. / Holzer, P. / Mobitz, H. / Scheufler, C. / Klumpp, M. / Tiedt, R. / Beyer, K.S. / Calkins, K. / Guthy, D. / ...Authors: Chen, C. / Zhu, H. / Stauffer, F. / Caravatti, G. / Vollmer, S. / Machauer, R. / Holzer, P. / Mobitz, H. / Scheufler, C. / Klumpp, M. / Tiedt, R. / Beyer, K.S. / Calkins, K. / Guthy, D. / Kiffe, M. / Zhang, J. / Gaul, C.
History
DepositionSep 17, 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

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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)77,9636
Polymers76,9132
Non-polymers1,0504
Water3,567198
1
A: Histone-lysine N-methyltransferase, H3 lysine-79 specific
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,9823
Polymers38,4571
Non-polymers5252
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)38,9823
Polymers38,4571
Non-polymers5252
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)158.140, 158.140, 73.980
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 / Fragment: UNP residues 2-332
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-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: K
#3: Chemical ChemComp-5EW / 6'-chloro-1,4-dimethyl-5'-(2-methyl-6-{[4-(methylamino)pyrimidin-2-yl]amino}-1H-indol-1-yl)-3,3'-bipyridin-2(1H)-one


Mass: 485.968 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H24ClN7O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 198 / 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: 3.47 Å3/Da / Density % sol: 64.57 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 1.4M K/Na tartrate tetrahydrate, 0.1M Hepes pH6.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99988 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: May 7, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99988 Å / Relative weight: 1
ReflectionResolution: 2.41→50 Å / Num. obs: 40943 / % possible obs: 100 % / Redundancy: 10.2 % / Biso Wilson estimate: 54.59 Å2 / Rmerge(I) obs: 0.082 / Net I/σ(I): 20.91
Reflection shellResolution: 2.41→2.47 Å / Redundancy: 9.3 % / Rmerge(I) obs: 0.867 / Mean I/σ(I) obs: 3.1 / % possible all: 99.8

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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: 2.41→45.65 Å / Cor.coef. Fo:Fc: 0.9475 / Cor.coef. Fo:Fc free: 0.9283 / SU R Cruickshank DPI: 0.215 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.21 / SU Rfree Blow DPI: 0.171 / SU Rfree Cruickshank DPI: 0.175
RfactorNum. reflection% reflectionSelection details
Rfree0.2015 2047 5 %RANDOM
Rwork0.172 ---
obs0.1734 40936 99.98 %-
Displacement parametersBiso mean: 62.83 Å2
Baniso -1Baniso -2Baniso -3
1-8.9179 Å20 Å20 Å2
2--8.9179 Å20 Å2
3----17.8357 Å2
Refine analyzeLuzzati coordinate error obs: 0.339 Å
Refinement stepCycle: 1 / Resolution: 2.41→45.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5050 0 72 198 5320
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015258HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.057155HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1742SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes121HARMONIC2
X-RAY DIFFRACTIONt_gen_planes760HARMONIC5
X-RAY DIFFRACTIONt_it5258HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.99
X-RAY DIFFRACTIONt_other_torsion17.35
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_contact6100SEMIHARMONIC4
LS refinement shellResolution: 2.41→2.47 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2623 150 4.99 %
Rwork0.2123 2854 -
all0.2147 3004 -
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)
13.8429-1.53650.3792.9946-0.17590.81480.0024-0.3483-0.15740.29960.0835-0.5466-0.09740.1411-0.0859-0.2071-0.0038-0.0525-0.1526-0.0059-0.108143.9418-7.98128.3859
23.5337-0.8829-0.68612.39970.20090.54530.0203-0.0801-0.3980.085-0.1374-0.39270.23450.020.117-0.13960.045-0.0232-0.17720.0663-0.08135.1942-37.06888.2272
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* L|* }
2X-RAY DIFFRACTION2{ B|* M|* }

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