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- PDB-7lzf: Crystal Structure of SETD2 bound to Compound 57 -

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Basic information

Entry
Database: PDB / ID: 7lzf
TitleCrystal Structure of SETD2 bound to Compound 57
ComponentsHistone-lysine N-methyltransferase SETD2
KeywordsTRANSFERASE
Function / homology
Function and homology information


mesoderm morphogenesis / coronary vasculature morphogenesis / morphogenesis of a branching structure / peptidyl-lysine trimethylation / cell migration involved in vasculogenesis / microtubule cytoskeleton organization involved in mitosis / [histone H3]-lysine36 N-trimethyltransferase / histone H3K36 trimethyltransferase activity / embryonic placenta morphogenesis / regulation of mRNA export from nucleus ...mesoderm morphogenesis / coronary vasculature morphogenesis / morphogenesis of a branching structure / peptidyl-lysine trimethylation / cell migration involved in vasculogenesis / microtubule cytoskeleton organization involved in mitosis / [histone H3]-lysine36 N-trimethyltransferase / histone H3K36 trimethyltransferase activity / embryonic placenta morphogenesis / regulation of mRNA export from nucleus / pericardium development / stem cell development / nucleosome organization / histone H3K36 methyltransferase activity / protein-lysine N-methyltransferase activity / response to type I interferon / embryonic cranial skeleton morphogenesis / positive regulation of ossification / response to alkaloid / regulation of protein localization to chromatin / response to metal ion / histone H3 methyltransferase activity / regulation of double-strand break repair via homologous recombination / endodermal cell differentiation / alpha-tubulin binding / positive regulation of interferon-alpha production / mismatch repair / positive regulation of autophagy / forebrain development / Transferases; Transferring one-carbon groups; Methyltransferases / regulation of cytokinesis / neural tube closure / transcription elongation by RNA polymerase II / stem cell differentiation / response to organic cyclic compound / PKMTs methylate histone lysines / chromosome / regulation of gene expression / angiogenesis / defense response to virus / regulation of DNA-templated transcription / nucleoplasm / nucleus / metal ion binding / cytoplasm
Similarity search - Function
Histone-lysine N-methyltransferase SETD2, animal / Set2 Rpb1 interacting domain / Set2 Rpb1 interacting domain superfamily / SRI (Set2 Rpb1 interacting) domain / SETD2/Set2, SET domain / AWS domain / AWS domain / AWS domain profile. / associated with SET domains / TFIIS/LEDGF domain superfamily ...Histone-lysine N-methyltransferase SETD2, animal / Set2 Rpb1 interacting domain / Set2 Rpb1 interacting domain superfamily / SRI (Set2 Rpb1 interacting) domain / SETD2/Set2, SET domain / AWS domain / AWS domain / AWS domain profile. / associated with SET domains / TFIIS/LEDGF domain superfamily / Cysteine-rich motif following a subset of SET domains / Post-SET domain / Post-SET domain profile. / WW domain / WW/rsp5/WWP domain signature. / WW domain superfamily / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / WW/rsp5/WWP domain profile. / Domain with 2 conserved Trp (W) residues / SET domain superfamily / WW domain / SET domain / SET domain profile. / SET domain
Similarity search - Domain/homology
S-ADENOSYLMETHIONINE / Chem-YHV / Histone-lysine N-methyltransferase SETD2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.47 Å
AuthorsFarrow, N.A. / Boriack-Sjodin, P.
CitationJournal: Acs Med.Chem.Lett. / Year: 2021
Title: Discovery of a First-in-Class Inhibitor of the Histone Methyltransferase SETD2 Suitable for Preclinical Studies.
Authors: Lampe, J.W. / Alford, J.S. / Boriak-Sjodin, P.A. / Brach, D. / Cosmopoulos, K. / Duncan, K.W. / Eckley, S.T. / Foley, M.A. / Harvey, D.M. / Motwani, V. / Munchhof, M.J. / Raimondi, A. / ...Authors: Lampe, J.W. / Alford, J.S. / Boriak-Sjodin, P.A. / Brach, D. / Cosmopoulos, K. / Duncan, K.W. / Eckley, S.T. / Foley, M.A. / Harvey, D.M. / Motwani, V. / Munchhof, M.J. / Raimondi, A. / Riera, T.V. / Tang, C. / Thomenius, M.J. / Totman, J. / Farrow, N.A.
History
DepositionMar 9, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 22, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 3, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: 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 SETD2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0637
Polymers31,9551
Non-polymers1,1076
Water66737
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.910, 76.648, 76.186
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 SETD2 / HIF-1 / Huntingtin yeast partner B / Huntingtin-interacting protein 1 / HIP-1 / Huntingtin- ...HIF-1 / Huntingtin yeast partner B / Huntingtin-interacting protein 1 / HIP-1 / Huntingtin-interacting protein B / Lysine N-methyltransferase 3A / Protein-lysine N-methyltransferase SETD2 / SET domain-containing protein 2 / hSET2 / p231HBP


Mass: 31955.488 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SETD2, HIF1, HYPB, KIAA1732, KMT3A, SET2, HSPC069 / Production host: Baculovirus expression vector pFastBac1-HM
References: UniProt: Q9BYW2, [histone H3]-lysine36 N-trimethyltransferase, Transferases; Transferring one-carbon groups; Methyltransferases

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Non-polymers , 5 types, 43 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE


Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N6O5S
#4: Chemical ChemComp-YHV / 4-fluoro-N-[(1R,3S)-3-{(3S)-3-[(methanesulfonyl)(methyl)amino]pyrrolidin-1-yl}cyclohexyl]-7-methyl-1H-indole-2-carboxamide


Mass: 450.570 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H31FN4O3S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 37 / 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: 2.28 Å3/Da / Density % sol: 46.06 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Potassium thiocyanate, 0.1 M Tris pH 7.5, 18% w/v PEG 2000 MME

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.953722 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 15, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.953722 Å / Relative weight: 1
ReflectionResolution: 2.47→41.82 Å / Num. obs: 10278 / % possible obs: 99.6 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.073 / Net I/σ(I): 15.9
Reflection shellResolution: 2.47→2.57 Å / Rmerge(I) obs: 0.64 / Mean I/σ(I) obs: 2.6 / Num. unique obs: 715

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5JLE

5jle


Resolution: 2.47→36.69 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.921 / SU B: 12.8 / SU ML: 0.262 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.535 / ESU R Free: 0.296 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.263 579 5.3 %RANDOM
Rwork0.2156 ---
obs0.2181 10278 99.39 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 125.84 Å2 / Biso mean: 62.722 Å2 / Biso min: 39.94 Å2
Baniso -1Baniso -2Baniso -3
1-5.4 Å20 Å2-0 Å2
2---6.96 Å20 Å2
3---1.56 Å2
Refinement stepCycle: final / Resolution: 2.47→36.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1929 0 65 37 2031
Biso mean--55.32 52.87 -
Num. residues----239
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0132057
X-RAY DIFFRACTIONr_bond_other_d0.0010.0181828
X-RAY DIFFRACTIONr_angle_refined_deg1.2351.6882762
X-RAY DIFFRACTIONr_angle_other_deg1.0711.6154251
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6495239
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.04122.097124
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.62615362
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.5431517
X-RAY DIFFRACTIONr_chiral_restr0.040.2249
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022295
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02451
LS refinement shellResolution: 2.473→2.537 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.249 26 -
Rwork0.32 715 -
all-741 -
obs--94.88 %

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