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- PDB-4ynd: The Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor... -

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Basic information

Entry
Database: PDB / ID: 4ynd
TitleThe Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2
ComponentsN-lysine methyltransferase SMYD2
KeywordsTransferase/Inhibitor / Epigenetics / SMYD2 / H3K36 / p53 / methyltransferase / lysine / Transferase-Inhibitor complex
Function / homology
Function and homology information


lysine N-methyltransferase activity / [histone H3]-lysine4 N-trimethyltransferase / peptidyl-lysine monomethylation / peptidyl-lysine dimethylation / histone H3K36 methyltransferase activity / histone H3K4 trimethyltransferase activity / protein-lysine N-methyltransferase activity / histone H3 methyltransferase activity / regulation of DNA damage response, signal transduction by p53 class mediator / RNA polymerase II complex binding ...lysine N-methyltransferase activity / [histone H3]-lysine4 N-trimethyltransferase / peptidyl-lysine monomethylation / peptidyl-lysine dimethylation / histone H3K36 methyltransferase activity / histone H3K4 trimethyltransferase activity / protein-lysine N-methyltransferase activity / histone H3 methyltransferase activity / regulation of DNA damage response, signal transduction by p53 class mediator / RNA polymerase II complex binding / Transferases; Transferring one-carbon groups; Methyltransferases / regulation of signal transduction by p53 class mediator / Regulation of TP53 Activity through Methylation / PKMTs methylate histone lysines / p53 binding / heart development / negative regulation of cell population proliferation / negative regulation of transcription by RNA polymerase II / nucleoplasm / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
SMYD2, SET domain / MYND finger / Zinc finger, MYND-type / Zinc finger MYND-type signature. / Zinc finger MYND-type profile. / Beta-clip-like / SET domain / Tetratricopeptide repeat domain / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily ...SMYD2, SET domain / MYND finger / Zinc finger, MYND-type / Zinc finger MYND-type signature. / Zinc finger MYND-type profile. / Beta-clip-like / SET domain / Tetratricopeptide repeat domain / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily / SET domain / SET domain profile. / SET domain / Beta Complex / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Alpha Horseshoe / Tetratricopeptide-like helical domain superfamily / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-4GQ / S-ADENOSYLMETHIONINE / N-lysine methyltransferase SMYD2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.79 Å
AuthorsSweis, R.F. / Wang, Z. / Algire, M. / Arrowsmith, C.H. / Brown, P.J. / Chiang, G.C. / Guo, J. / Jakob, C.G. / Kennedy, S. / Li, F. ...Sweis, R.F. / Wang, Z. / Algire, M. / Arrowsmith, C.H. / Brown, P.J. / Chiang, G.C. / Guo, J. / Jakob, C.G. / Kennedy, S. / Li, F. / Soni, N.B. / Vedadi, M. / Pappano, W.N.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2.
Authors: Sweis, R.F. / Wang, Z. / Algire, M. / Arrowsmith, C.H. / Brown, P.J. / Chiang, G.G. / Guo, J. / Jakob, C.G. / Kennedy, S. / Li, F. / Maag, D. / Shaw, B. / Soni, N.B. / Vedadi, M. / Pappano, W.N.
History
DepositionMar 9, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 20, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 8, 2015Group: Database references
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Source and taxonomy / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity_src_gen / pdbx_initial_refinement_model / pdbx_struct_oper_list / struct_keywords
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation / _struct_keywords.pdbx_keywords / _struct_keywords.text

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: N-lysine methyltransferase SMYD2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,3786
Polymers53,2061
Non-polymers1,1725
Water2,360131
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area20640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.796, 71.301, 118.930
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein N-lysine methyltransferase SMYD2 / HSKM-B / Histone methyltransferase SMYD2 / Lysine N-methyltransferase 3C / SET and MYND domain- ...HSKM-B / Histone methyltransferase SMYD2 / Lysine N-methyltransferase 3C / SET and MYND domain-containing protein 2


Mass: 53205.793 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SMYD2, KMT3C / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9NRG4, Transferases; Transferring one-carbon groups; Methyltransferases, histone-lysine N-methyltransferase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-4GQ / N-cyclohexyl-N~3~-[2-(3,4-dichlorophenyl)ethyl]-N-(2-{[(2R)-2-hydroxy-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)ethyl]amino}ethyl)-beta-alaninamide


Mass: 577.542 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H38Cl2N4O4
#4: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE / S-Adenosyl methionine


Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N6O5S
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 131 / 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: 2.1 Å3/Da / Density % sol: 41.53 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop
Details: The protein ligand complex was made using a slight molar excess of S adenomethionine (SAM) and A-893 from concentrated DMSO stocks. Co-crystals were grown using the hanging drop format with ...Details: The protein ligand complex was made using a slight molar excess of S adenomethionine (SAM) and A-893 from concentrated DMSO stocks. Co-crystals were grown using the hanging drop format with a 1:1 v/v drop composition of the protein complex: well solution (20% w/v PEG 10,000, 0.1 HEPES pH 7.5) at 17C.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 21, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.79→118.938 Å / Num. obs: 11772 / % possible obs: 100 % / Redundancy: 6.4 % / Biso Wilson estimate: 52.64 Å2 / Rmerge(I) obs: 0.155 / Net I/σ(I): 13.7
Reflection shellResolution: 2.79→2.796 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.563 / Mean I/σ(I) obs: 4.8 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3S7B

3s7b


Resolution: 2.79→45.67 Å / Cor.coef. Fo:Fc: 0.9056 / Cor.coef. Fo:Fc free: 0.8321 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.397
RfactorNum. reflection% reflectionSelection details
Rfree0.2532 552 4.72 %RANDOM
Rwork0.1979 ---
obs0.2004 11691 99.89 %-
Displacement parametersBiso mean: 33.04 Å2
Baniso -1Baniso -2Baniso -3
1--3.7307 Å20 Å20 Å2
2--5.3312 Å20 Å2
3----1.6005 Å2
Refine analyzeLuzzati coordinate error obs: 0.324 Å
Refinement stepCycle: LAST / Resolution: 2.79→45.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3433 0 69 131 3633
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0073582HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.934831HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1268SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes90HARMONIC2
X-RAY DIFFRACTIONt_gen_planes529HARMONIC5
X-RAY DIFFRACTIONt_it3582HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion1.96
X-RAY DIFFRACTIONt_other_torsion19.5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion443SEMIHARMONIC5
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_contact4039SEMIHARMONIC4
LS refinement shellResolution: 2.79→3.06 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.2512 140 5.11 %
Rwork0.2168 2599 -
all0.2186 2739 -
obs--99.89 %

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