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- PDB-5dt2: Crystal structure of Dot1L in complex with inhibitor CPD11 [N4-me... -

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Basic information

Entry
Database: PDB / ID: 5dt2
TitleCrystal structure of Dot1L in complex with inhibitor CPD11 [N4-methyl-N2-(2-methyl-1-(2-phenoxyphenyl)-1H-indol-6-yl)pyrimidine-2,4-diamine]
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 / subtelomeric heterochromatin formation / telomere organization / DNA damage checkpoint signaling ...[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 / subtelomeric heterochromatin formation / telomere organization / DNA damage checkpoint signaling / PKMTs methylate histone lysines / methylation / gene expression / nucleic acid binding / RNA polymerase II-specific DNA-binding transcription factor binding / transcription coactivator activity / chromosome, telomeric region / DNA repair / intracellular membrane-bounded organelle / 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-5EV / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 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)78,1408
Polymers76,9132
Non-polymers1,2276
Water4,306239
1
A: Histone-lysine N-methyltransferase, H3 lysine-79 specific
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,0704
Polymers38,4571
Non-polymers6143
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)39,0704
Polymers38,4571
Non-polymers6143
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)158.320, 158.320, 74.570
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-5EV / N~4~-methyl-N~2~-[2-methyl-1-(2-phenoxyphenyl)-1H-indol-6-yl]pyrimidine-2,4-diamine


Mass: 421.494 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H23N5O
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 239 / 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: 3.51 Å3/Da / Density % sol: 64.93 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 1.4M lithium sulfate 0.1M sodium citrate tribasic dihydrate 0.3M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99998 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Jun 16, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99998 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 47515 / % possible obs: 100 % / Redundancy: 10.2 % / Biso Wilson estimate: 49.9 Å2 / Rmerge(I) obs: 0.108 / Net I/σ(I): 15.82
Reflection shellResolution: 2.3→2.36 Å / Redundancy: 9.4 % / Rmerge(I) obs: 1.177 / Mean I/σ(I) obs: 2.33 / % possible all: 99.9

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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: 2.3→45.7 Å / Cor.coef. Fo:Fc: 0.9402 / Cor.coef. Fo:Fc free: 0.9217 / SU R Cruickshank DPI: 0.19 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.188 / SU Rfree Blow DPI: 0.161 / SU Rfree Cruickshank DPI: 0.164
RfactorNum. reflection% reflectionSelection details
Rfree0.2131 2376 5 %RANDOM
Rwork0.184 ---
obs0.1855 47513 99.96 %-
Displacement parametersBiso mean: 58.16 Å2
Baniso -1Baniso -2Baniso -3
1-9.8594 Å20 Å20 Å2
2--9.8594 Å20 Å2
3----19.7189 Å2
Refine analyzeLuzzati coordinate error obs: 0.328 Å
Refinement stepCycle: 1 / Resolution: 2.3→45.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4998 0 84 239 5321
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015212HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.027080HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1743SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes124HARMONIC2
X-RAY DIFFRACTIONt_gen_planes744HARMONIC5
X-RAY DIFFRACTIONt_it5212HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.24
X-RAY DIFFRACTIONt_other_torsion17.44
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion664SEMIHARMONIC5
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_contact6024SEMIHARMONIC4
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2143 175 4.99 %
Rwork0.2209 3333 -
all0.2205 3508 -
obs--99.96 %
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)
13.7376-1.97040.51963.7188-0.33730.6467-0.0109-0.3387-0.00210.34450.0584-0.4561-0.10650.0831-0.0476-0.1778-0.002-0.0253-0.1471-0.0213-0.148143.9396-8.19568.2217
23.0211-0.8474-0.76182.24410.24560.54380.0125-0.1481-0.26140.1336-0.0787-0.35060.1798-0.0090.0662-0.14570.0221-0.0628-0.16090.0372-0.051535.2565-37.02878.3167
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* L|* }
2X-RAY DIFFRACTION2{ B|* M|* }

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