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- PDB-6zrb: Crystal structure of SMYD3 conjugate with piperidine-based covale... -

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Basic information

Entry
Database: PDB / ID: 6zrb
TitleCrystal structure of SMYD3 conjugate with piperidine-based covalent inhibitor EM127
ComponentsHistone-lysine N-methyltransferase SMYD3
KeywordsONCOPROTEIN / Inhibitor / covalent inhibitor / complex / methyltransferase
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 / nucleus / metal ion binding / cytosol
Similarity search - Function
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. / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily / SET domain ...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. / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily / SET domain / SET domain profile. / SET domain / Tetratricopeptide-like helical domain superfamily
Similarity search - Domain/homology
ACETATE ION / Chem-QON / S-ADENOSYLMETHIONINE / Histone-lysine N-methyltransferase SMYD3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsTalibov, V.O. / Eriksson, D.
Funding support Italy, 1items
OrganizationGrant numberCountry
Italian Association for Cancer ResearchIG 19172 Italy
CitationJournal: Eur.J.Med.Chem. / Year: 2022
Title: Discovery of the 4-aminopiperidine-based compound EM127 for the site-specific covalent inhibition of SMYD3
Authors: Parenti, M.D. / Naldi, M. / Manoni, E. / Fabini, E. / Cederfelt, D. / Talibov, V.O. / Gressani, V. / Guven, U. / Grossi, V. / Fasano, C. / Sanese, P. / De Marco, K. / Shtil, A.A. / Kurkin, A. ...Authors: Parenti, M.D. / Naldi, M. / Manoni, E. / Fabini, E. / Cederfelt, D. / Talibov, V.O. / Gressani, V. / Guven, U. / Grossi, V. / Fasano, C. / Sanese, P. / De Marco, K. / Shtil, A.A. / Kurkin, A.V. / Altieri, A. / Danielson, U.H. / Caretti, G. / Simone, C. / Varchi, G. / Bartolini, M. / Del Rio, A.
History
DepositionJul 13, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 27, 2022Provider: repository / Type: Initial release
Revision 1.1Sep 14, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)50,4267
Polymers49,4601
Non-polymers9656
Water7,422412
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area140 Å2
ΔGint-0 kcal/mol
Surface area19820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.935, 65.989, 107.318
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 49460.402 Da / Num. of mol.: 1 / Mutation: K13N, K140R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SMYD3, ZMYND1, ZNFN3A1 / Plasmid: pET15b
Details (production host): N-term 6xHis tag, thrombin cleavage
Production host: Escherichia coli (E. coli)
References: UniProt: Q9H7B4, [histone H3]-lysine4 N-trimethyltransferase

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Non-polymers , 5 types, 418 molecules

#2: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE


Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N6O5S
#3: Chemical ChemComp-QON / N-[1-(2-Chloroacetyl)piperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide / ~{N}-[1-(2-chloranylethanoyl)piperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide


Mass: 311.764 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H18ClN3O3
#4: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 412 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.21 Å3/Da / Density % sol: 44.33 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.25
Details: Protein was pre-incubated with the covalent inhibitor, 7 mg/mL and 0.4 mM, respectively, for 8 h at RT. Crystallization was performed in 2 uL hanging drops, 1:1 protein to reservoir ratio, ...Details: Protein was pre-incubated with the covalent inhibitor, 7 mg/mL and 0.4 mM, respectively, for 8 h at RT. Crystallization was performed in 2 uL hanging drops, 1:1 protein to reservoir ratio, reservoir: 16% PEG3350, 100 mM Tris (pH 8.25), 100 mM Mg(OAc)2). Protein crystals were cryoprotected in 20% PEG3350, 100 mM Tris (pH 8.25), 100 mM Mg(OAc)2, 10% DMSO and 10% glycerol.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 0.918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 11, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.918 Å / Relative weight: 1
ReflectionResolution: 1.55→107.32 Å / Num. obs: 62691 / % possible obs: 98.7 % / Redundancy: 5 % / CC1/2: 0.999 / Rmerge(I) obs: 0.052 / Rpim(I) all: 0.025 / Rrim(I) all: 0.057 / Net I/σ(I): 16.4
Reflection shellResolution: 1.55→1.58 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.45 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 2667 / CC1/2: 0.789 / Rpim(I) all: 0.277 / Rrim(I) all: 0.532 / % possible all: 86.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6Z2R

6z2r
PDB Unreleased entry


Resolution: 1.55→56.28 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.962 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.078 / ESU R Free: 0.075 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1845 3106 5 %RANDOM
Rwork0.1654 ---
obs0.1664 59518 98.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 73.88 Å2 / Biso mean: 21.465 Å2 / Biso min: 11.64 Å2
Baniso -1Baniso -2Baniso -3
1-1.14 Å2-0 Å20 Å2
2---0.39 Å2-0 Å2
3----0.75 Å2
Refinement stepCycle: final / Resolution: 1.55→56.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3402 0 54 412 3868
Biso mean--19.05 30.76 -
Num. residues----425
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0133540
X-RAY DIFFRACTIONr_bond_other_d0.0350.0173343
X-RAY DIFFRACTIONr_angle_refined_deg1.5171.6534777
X-RAY DIFFRACTIONr_angle_other_deg2.3161.5857781
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0935431
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.97321.771192
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.6415662
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.3461529
X-RAY DIFFRACTIONr_chiral_restr0.0830.2449
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.023911
X-RAY DIFFRACTIONr_gen_planes_other0.0110.02736
X-RAY DIFFRACTIONr_mcbond_it1.4012.0531711
X-RAY DIFFRACTIONr_mcbond_other1.4022.0511710
X-RAY DIFFRACTIONr_mcangle_it2.2063.0742136
LS refinement shellResolution: 1.55→1.59 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.24 189 -
Rwork0.236 3848 -
all-4037 -
obs--87.55 %

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