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- PDB-5mw4: Crystal structure of Dot1L in complex with inhibitor CPD7 [N-(3-(... -

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Basic information

Entry
Database: PDB / ID: 5mw4
TitleCrystal structure of Dot1L in complex with inhibitor CPD7 [N-(3-(((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)(methyl)amino)propyl)-2-(3-(2-chloro-3-(2-methylpyridin-3-yl)benzo[b]thiophen-5-yl)ureido)acetamide]
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-5JU / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.19 Å
AuthorsBe, C. / Koch, E. / Gaul, C. / Stauffer, F. / Moebitz, H. / Scheufler, C.
CitationJournal: ACS Med Chem Lett / Year: 2017
Title: Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.
Authors: Mobitz, H. / Machauer, R. / Holzer, P. / Vaupel, A. / Stauffer, F. / Ragot, C. / Caravatti, G. / Scheufler, C. / Fernandez, C. / Hommel, U. / Tiedt, R. / Beyer, K.S. / Chen, C. / Zhu, H. / Gaul, C.
History
DepositionJan 18, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 22, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2017Group: Database references
Revision 1.2Jan 17, 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)78,5908
Polymers76,9132
Non-polymers1,6776
Water4,990277
1
A: Histone-lysine N-methyltransferase, H3 lysine-79 specific
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,2954
Polymers38,4571
Non-polymers8383
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)39,2954
Polymers38,4571
Non-polymers8383
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)158.360, 158.360, 74.590
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-5JU / N~2~-{[2-chloro-3-(2-methylpyridin-3-yl)-1-benzothiophen-5-yl]carbamoyl}-N-(3-{methyl[(3R)-1-(5H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl]amino}propyl)glycinamide


Mass: 646.205 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H36ClN9O2S
#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.: 277 / Source method: isolated from a natural source / Formula: H2O

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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: 3.51 Å3/Da / Density % sol: 64.96 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 0.92M Lithium sulfate monohydrate, 0.1M Ammonium sulfate, 0.1M Sodium citrate tribasic dihydrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99999 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 8, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 2.19→50 Å / Num. all: 55017 / Num. obs: 54968 / % possible obs: 99.9 % / Redundancy: 10.3 % / Biso Wilson estimate: 47.35 Å2 / Rsym value: 0.097 / Net I/σ(I): 15.35
Reflection shellResolution: 2.19→2.25 Å / Redundancy: 9.5 % / Mean I/σ(I) obs: 2.05 / % possible all: 99.2

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1nw3

1nw3


Resolution: 2.19→45.72 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.944 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.159 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.158 / SU Rfree Blow DPI: 0.136 / SU Rfree Cruickshank DPI: 0.137
RfactorNum. reflection% reflectionSelection details
Rfree0.202 2749 5 %RANDOM
Rwork0.184 ---
obs0.184 54967 99.9 %-
Displacement parametersBiso mean: 64.41 Å2
Baniso -1Baniso -2Baniso -3
1-7.6748 Å20 Å20 Å2
2--7.6748 Å20 Å2
3----15.3497 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: 1 / Resolution: 2.19→45.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4899 0 110 277 5286
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015135HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.016978HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1727SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes124HARMONIC2
X-RAY DIFFRACTIONt_gen_planes736HARMONIC5
X-RAY DIFFRACTIONt_it5135HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.19
X-RAY DIFFRACTIONt_other_torsion17.31
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion652SEMIHARMONIC5
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_contact5921SEMIHARMONIC4
LS refinement shellResolution: 2.19→2.25 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.282 200 5 %
Rwork0.232 3799 -
all0.234 3999 -
obs--99.21 %
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)
14.5436-2.51990.51693.9668-0.32010.6908-0.1649-0.4836-0.11640.4670.2204-0.4781-0.13830.1548-0.0555-0.2250.0191-0.031-0.1592-0.0221-0.127644.1748-7.86848.2287
23.5283-1.2368-0.90862.71180.30530.5866-0.0013-0.0762-0.26310.0729-0.0863-0.4070.22280.02340.0875-0.18650.0567-0.0327-0.19690.0282-0.030535.2567-37.32998.27
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* L|* }
2X-RAY DIFFRACTION2{ B|* M|* }

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