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- PDB-5dry: Crystal structure of Dot1L in complex with inhibitor CPD3 [N-(1-(... -

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Basic information

Entry
Database: PDB / ID: 5dry
TitleCrystal structure of Dot1L in complex with inhibitor CPD3 [N-(1-(2-chlorophenyl)-1H-indol-6-yl)-2-(2-(5-(2-chlorophenyl)-1H-tetrazol-1-yl)acetyl)hydrazinecarboxamide]
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
Chem-5EK / : / 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 16, 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 ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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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)78,0346
Polymers76,9132
Non-polymers1,1214
Water5,441302
1
A: Histone-lysine N-methyltransferase, H3 lysine-79 specific
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,0173
Polymers38,4571
Non-polymers5602
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)39,0173
Polymers38,4571
Non-polymers5602
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)158.760, 158.760, 74.460
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 2-333
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-5EK / N-[1-(2-chlorophenyl)-1H-indol-6-yl]-2-{[5-(2-chlorophenyl)-1H-tetrazol-1-yl]acetyl}hydrazinecarboxamide


Mass: 521.358 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H18Cl2N8O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 302 / 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: 3.52 Å3/Da / Density % sol: 65.08 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 1.2M K/Na tartrate 0.1M Hepes pH7.2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99997 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: May 23, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99997 Å / Relative weight: 1
ReflectionResolution: 2.41→50 Å / Num. obs: 41501 / % possible obs: 100 % / Redundancy: 10.2 % / Biso Wilson estimate: 53.33 Å2 / Rmerge(I) obs: 0.097 / Net I/σ(I): 18.85
Reflection shellResolution: 2.41→2.47 Å / Redundancy: 9.7 % / Mean I/σ(I) obs: 2.78 / Num. measured obs: 3065 / % 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: 2.41→45.83 Å / Cor.coef. Fo:Fc: 0.9464 / Cor.coef. Fo:Fc free: 0.9408 / SU R Cruickshank DPI: 0.225 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.225 / SU Rfree Blow DPI: 0.172 / SU Rfree Cruickshank DPI: 0.174
RfactorNum. reflection% reflectionSelection details
Rfree0.199 2075 5 %RANDOM
Rwork0.1771 ---
obs0.1781 41500 99.99 %-
Displacement parametersBiso mean: 55.24 Å2
Baniso -1Baniso -2Baniso -3
1-5.7727 Å20 Å20 Å2
2--5.7727 Å20 Å2
3----11.5455 Å2
Refine analyzeLuzzati coordinate error obs: 0.313 Å
Refinement stepCycle: 1 / Resolution: 2.41→45.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5110 0 74 302 5486
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015321HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.067236HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1789SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes131HARMONIC2
X-RAY DIFFRACTIONt_gen_planes767HARMONIC5
X-RAY DIFFRACTIONt_it5321HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.08
X-RAY DIFFRACTIONt_other_torsion18.27
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion678SEMIHARMONIC5
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_contact6013SEMIHARMONIC4
LS refinement shellResolution: 2.41→2.47 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2528 152 4.98 %
Rwork0.2243 2902 -
all0.2256 3054 -
obs--99.99 %
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)
13.2012-1.61040.34452.7435-0.1720.745-0.0107-0.2042-0.14790.22210.0884-0.4272-0.07950.1522-0.0777-0.1757-0.0062-0.0397-0.1319-0.0002-0.094444.2137-8.23188.4957
23.1178-1.3245-0.68532.51450.14020.53890.0445-0.1145-0.24850.0375-0.1042-0.38170.19490.04910.0598-0.13750.0316-0.0178-0.15060.0411-0.068235.6781-37.20938.382
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* L|* }
2X-RAY DIFFRACTION2{ B|* M|* }

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