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- PDB-6ijl: Crystal structure of SmyD3 in complex with covalent inhibitor 5 -

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Basic information

Entry
Database: PDB / ID: 6ijl
TitleCrystal structure of SmyD3 in complex with covalent inhibitor 5
ComponentsHistone-lysine N-methyltransferase SMYD3
KeywordsTRANSFERASE/INHIBITOR / covalent inhibitor / methyltransferase / methyltransferase inhibitor / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


histone H3K36 dimethyltransferase activity / histone H4 methyltransferase activity / [histone H3]-lysine4 N-trimethyltransferase / myotube cell development / histone H3K4 trimethyltransferase activity / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / RNA polymerase II complex binding / cellular response to dexamethasone stimulus / establishment of protein localization / PKMTs methylate histone lysines ...histone H3K36 dimethyltransferase activity / histone H4 methyltransferase activity / [histone H3]-lysine4 N-trimethyltransferase / myotube cell development / histone H3K4 trimethyltransferase activity / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / RNA polymerase II complex binding / cellular response to dexamethasone stimulus / establishment of protein localization / PKMTs methylate histone lysines / nucleosome assembly / positive regulation of peptidyl-serine phosphorylation / methylation / RNA polymerase II cis-regulatory region sequence-specific DNA binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / metal ion binding / nucleus / cytosol
Similarity search - Function
Annexin V; domain 1 - #160 / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat - #970 / Helix Hairpins - #2220 / Histone-lysine N-methyltransferase Smyd3 / SMYD3, SET domain / Histone-lysine N-methyltransferase (EC 2.1.1.43) family profile. / MYND finger / Zinc finger, MYND-type / Zinc finger MYND-type signature. / Zinc finger MYND-type profile. ...Annexin V; domain 1 - #160 / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat - #970 / Helix Hairpins - #2220 / Histone-lysine N-methyltransferase Smyd3 / SMYD3, SET domain / Histone-lysine N-methyltransferase (EC 2.1.1.43) family profile. / MYND finger / Zinc finger, MYND-type / Zinc finger MYND-type signature. / Zinc finger MYND-type profile. / Annexin V; domain 1 / Beta-clip-like / SET domain / Tetratricopeptide repeat domain / Helix Hairpins / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily / SET domain / SET domain profile. / SET domain / Beta Complex / Helix non-globular / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Special / Alpha Horseshoe / Tetratricopeptide-like helical domain superfamily / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-A8U / S-ADENOSYLMETHIONINE / Histone-lysine N-methyltransferase SMYD3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.351 Å
AuthorsBaburajendran, N. / Joy, J.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3.
Authors: Huang, C. / Liew, S.S. / Lin, G.R. / Poulsen, A. / Ang, M.J.Y. / Chia, B.C.S. / Chew, S.Y. / Kwek, Z.P. / Wee, J.L.K. / Ong, E.H. / Retna, P. / Baburajendran, N. / Li, R. / Yu, W. / Koh- ...Authors: Huang, C. / Liew, S.S. / Lin, G.R. / Poulsen, A. / Ang, M.J.Y. / Chia, B.C.S. / Chew, S.Y. / Kwek, Z.P. / Wee, J.L.K. / Ong, E.H. / Retna, P. / Baburajendran, N. / Li, R. / Yu, W. / Koh-Stenta, X. / Ngo, A. / Manesh, S. / Fulwood, J. / Ke, Z. / Chung, H.H. / Sepramaniam, S. / Chew, X.H. / Dinie, N. / Lee, M.A. / Chew, Y.S. / Low, C.B. / Pendharkar, V. / Manoharan, V. / Vuddagiri, S. / Sangthongpitag, K. / Joy, J. / Matter, A. / Hill, J. / Keller, T.H. / Foo, K.
History
DepositionOct 10, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 14, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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 SMYD3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,2456
Polymers49,1781
Non-polymers1,0675
Water1,802100
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area19490 Å2
Unit cell
Length a, b, c (Å)61.212, 66.232, 107.397
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Histone-lysine N-methyltransferase SMYD3 / SET and MYND domain-containing protein 3


Mass: 49178.121 Da / Num. of mol.: 1 / Mutation: K13N, K140R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SMYD3 / Production host: Escherichia coli (E. coli)
References: UniProt: Q9H7B4, histone-lysine N-methyltransferase
#2: Chemical ChemComp-A8U / propyl (2~{R})-4-[2-[4-(1-azanylcyclopropyl)phenyl]quinolin-7-yl]carbonyl-2-methyl-piperazine-1-carboxylate


Mass: 472.579 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H32N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#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.: 100 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.24 Å3/Da / Density % sol: 45.08 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.2M Magnesium acetate, 17% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Apr 3, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.35→50 Å / Num. obs: 18706 / % possible obs: 99.3 % / Redundancy: 6.9 % / Biso Wilson estimate: 25.51 Å2 / Rmerge(I) obs: 0.136 / Rpim(I) all: 0.055 / Rrim(I) all: 0.147 / Χ2: 0.973 / Net I/σ(I): 8.1 / Num. measured all: 128300
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.35-2.395.80.2738130.9620.120.2990.79889
2.39-2.437.10.3189360.9640.1280.3440.85100
2.43-2.487.10.2679210.9710.1070.2880.961100
2.48-2.537.20.2269150.970.090.2440.91100
2.53-2.597.10.2869290.9750.1150.3090.925100
2.59-2.656.90.4799260.9670.1950.5181.233100
2.65-2.717.10.2869110.9140.1150.3090.733100
2.71-2.7970.2619490.9870.1060.2821.041100
2.79-2.877.20.1689180.9890.0670.1810.948100
2.87-2.967.20.1379210.9920.0550.1481.01100
2.96-3.077.20.1289350.9930.0510.1381.13100
3.07-3.197.10.1279340.9930.0510.1371.032100
3.19-3.336.80.1059520.9930.0430.1131.31299.9
3.33-3.516.60.1789250.9710.0720.1920.839100
3.51-3.736.10.1769260.9590.0720.190.81698.2
3.73-4.026.40.1659430.9690.0660.1780.79699.6
4.02-4.426.90.0629620.9980.0250.0681.021100
4.42-5.067.10.0579630.9980.0230.0610.881100
5.06-6.3770.069750.9980.0240.0651.267100
6.37-506.40.04910520.9980.020.0530.84999.8

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data scaling
PDB_EXTRACT3.24data extraction
Cootmodel building
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.351→41.712 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 30.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.316 1811 9.98 %
Rwork0.2809 16335 -
obs0.2845 18146 96.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 84.25 Å2 / Biso mean: 27.8926 Å2 / Biso min: 11.72 Å2
Refinement stepCycle: final / Resolution: 2.351→41.712 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3319 0 65 100 3484
Biso mean--35.22 23.35 -
Num. residues----423
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073477
X-RAY DIFFRACTIONf_angle_d1.2884690
X-RAY DIFFRACTIONf_chiral_restr0.048521
X-RAY DIFFRACTIONf_plane_restr0.007602
X-RAY DIFFRACTIONf_dihedral_angle_d16.9981301
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.3513-2.41490.33671370.2752118294
2.4149-2.48590.39241300.31241277100
2.4859-2.56610.34351580.31441286100
2.5661-2.65790.45321190.4054114789
2.6579-2.76420.47551240.3963117291
2.7642-2.890.35511390.30681278100
2.89-3.04230.32591500.28551275100
3.0423-3.23290.34251340.2908129499
3.2329-3.48240.37611430.3118121093
3.4824-3.83260.35881260.3371120492
3.8326-4.38670.27341480.2485127698
4.3867-5.52470.20471470.19631327100
5.5247-41.7120.19411560.18231407100
Refinement TLS params.Method: refined / Origin x: 73.5347 Å / Origin y: 131.9699 Å / Origin z: 120.3688 Å
111213212223313233
T0.1432 Å2-0.0048 Å20.0049 Å2-0.1528 Å20.0041 Å2--0.1471 Å2
L0.5601 °2-0.2799 °2-0.1661 °2-0.8639 °20.3349 °2--0.5661 °2
S0.0462 Å °0.0602 Å °0.0599 Å °-0.1052 Å °-0.009 Å °-0.0522 Å °-0.0571 Å °0.0362 Å °-0.0308 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA3 - 425
2X-RAY DIFFRACTION1allB3
3X-RAY DIFFRACTION1allC4 - 6
4X-RAY DIFFRACTION1allS1 - 100
5X-RAY DIFFRACTION1allD1

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