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- PDB-5lsy: Structure of the Epigenetic Oncogene MMSET and inhibition by N-Al... -

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Basic information

Entry
Database: PDB / ID: 5lsy
TitleStructure of the Epigenetic Oncogene MMSET and inhibition by N-Alkyl Sinefungin Derivatives
ComponentsHistone-lysine N-methyltransferase SETD2
KeywordsTRANSFERASE / lysine methyltransferase SETD2 SET domain / SETD2#1
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 / pericardium development ...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 / pericardium development / regulation of mRNA export from nucleus / stem cell development / histone H3K36 methyltransferase activity / nucleosome organization / embryonic cranial skeleton morphogenesis / protein-lysine N-methyltransferase activity / response to type I interferon / 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 / positive regulation of interferon-alpha production / alpha-tubulin binding / mismatch repair / positive regulation of autophagy / forebrain development / Transferases; Transferring one-carbon groups; Methyltransferases / regulation of cytokinesis / neural tube closure / stem cell differentiation / transcription elongation by RNA polymerase II / response to organic cyclic compound / PKMTs methylate histone lysines / chromosome / regulation of gene expression / defense response to virus / angiogenesis / regulation of DNA-templated transcription / nucleoplasm / nucleus / metal ion binding / cytoplasm
Similarity search - Function
Histone-lysine N-methyltransferase SETD2, animal / Set2 Rpb1 interacting domain superfamily / SETD2/Set2, SET domain / Set2 Rpb1 interacting domain / SRI (Set2 Rpb1 interacting) 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 superfamily / SETD2/Set2, SET domain / Set2 Rpb1 interacting domain / SRI (Set2 Rpb1 interacting) 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 / WW domain / SET domain / SET domain superfamily / SET domain profile. / SET domain
Similarity search - Domain/homology
Chem-76M / THIOCYANATE ION / Histone-lysine N-methyltransferase SETD2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.62 Å
AuthorsTisi, D. / Pathuri, P. / Heightman, T.
CitationJournal: ACS Chem. Biol. / Year: 2016
Title: Structure of the Epigenetic Oncogene MMSET and Inhibition by N-Alkyl Sinefungin Derivatives.
Authors: Tisi, D. / Chiarparin, E. / Tamanini, E. / Pathuri, P. / Coyle, J.E. / Hold, A. / Holding, F.P. / Amin, N. / Martin, A.C. / Rich, S.J. / Berdini, V. / Yon, J. / Acklam, P. / Burke, R. / ...Authors: Tisi, D. / Chiarparin, E. / Tamanini, E. / Pathuri, P. / Coyle, J.E. / Hold, A. / Holding, F.P. / Amin, N. / Martin, A.C. / Rich, S.J. / Berdini, V. / Yon, J. / Acklam, P. / Burke, R. / Drouin, L. / Harmer, J.E. / Jeganathan, F. / van Montfort, R.L. / Newbatt, Y. / Tortorici, M. / Westlake, M. / Wood, A. / Hoelder, S. / Heightman, T.D.
History
DepositionSep 5, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 12, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 21, 2016Group: Database references
Revision 1.2Oct 16, 2019Group: Data collection / Category: reflns_shell
Revision 1.3Jan 17, 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 / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id

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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)34,7936
Polymers34,0991
Non-polymers6945
Water7,296405
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area250 Å2
ΔGint-29 kcal/mol
Surface area15140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.983, 61.504, 77.308
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 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 / SET domain-containing protein 2 / hSET2 / p231HBP


Mass: 34098.812 Da / Num. of mol.: 1 / Fragment: UNP residues 1433-1711
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SETD2, HIF1, HYPB, KIAA1732, KMT3A, SET2, HSPC069 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Codon Plus RIL
References: UniProt: Q9BYW2, 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-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CNS
#4: Chemical ChemComp-76M / [(2~{S},5~{R})-1-[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]-5-azaniumyl-6-oxidanyl-6-oxidanylidene-hexan-2-yl]-(2-methylpropyl)azanium


Mass: 439.509 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H33N7O5
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 405 / Source method: isolated from a natural source / Formula: H2O

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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: 2.06 Å3/Da / Density % sol: 40.18 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 0.1M Hepes, PH7.3, 0.1MKSCN, 25-30%MPEG2000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jun 17, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.62→46.893 Å / Num. obs: 182683 / % possible obs: 90.9 % / Redundancy: 5.3 % / Net I/σ(I): 13.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0131refinement
XDSdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 3OOI

3ooi


Resolution: 1.62→46.89 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.937 / SU B: 3.856 / SU ML: 0.073 / Cross valid method: THROUGHOUT / ESU R: 0.103 / ESU R Free: 0.101 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21469 1659 5 %RANDOM
Rwork0.1813 ---
obs0.18304 31691 90.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 20.258 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å20 Å2-0 Å2
2--0.06 Å2-0 Å2
3----0.05 Å2
Refinement stepCycle: 1 / Resolution: 1.62→46.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1964 0 37 405 2406
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0192090
X-RAY DIFFRACTIONr_bond_other_d0.0020.021932
X-RAY DIFFRACTIONr_angle_refined_deg1.4831.9492821
X-RAY DIFFRACTIONr_angle_other_deg0.9392.9754464
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0235257
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.47823.832107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.14615.314382
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.5931518
X-RAY DIFFRACTIONr_chiral_restr0.0920.2291
X-RAY DIFFRACTIONr_gen_planes_refined00.0212393
X-RAY DIFFRACTIONr_gen_planes_other00.021508
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.2562.0021002
X-RAY DIFFRACTIONr_mcbond_other1.1931.9921000
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.782.3811088
X-RAY DIFFRACTIONr_scbond_other1.782.3811088
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined4.6914.793764
X-RAY DIFFRACTIONr_long_range_B_other4.6874.791765
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.616→1.658 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.325 70 -
Rwork0.328 1375 -
obs--54.08 %
Refinement TLS params.Method: refined / Origin x: 8.8508 Å / Origin y: 23.4739 Å / Origin z: 30.9312 Å
111213212223313233
T0.0222 Å2-0.0074 Å20.0031 Å2-0.0262 Å20.0021 Å2--0.002 Å2
L1.9038 °2-0.8318 °20.1058 °2-1.554 °2-0.0705 °2--0.7917 °2
S0.0256 Å °0.1886 Å °0.043 Å °-0.0292 Å °-0.0144 Å °-0.0413 Å °-0.1283 Å °0.0626 Å °-0.0112 Å °

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