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- PDB-8cnm: Human Sirt6 in complex with the inhibitor S6020 and ADP-ribose -

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Basic information

Entry
Database: PDB / ID: 8cnm
TitleHuman Sirt6 in complex with the inhibitor S6020 and ADP-ribose
ComponentsNAD-dependent protein deacetylase sirtuin-6
KeywordsHYDROLASE / Deacylase / Inhibitor
Function / homology
Function and homology information


NAD-dependent histone H3K56 deacetylase activity / NAD-dependent histone H3K18 deacetylase activity / ketone biosynthetic process / NAD-dependent histone H3K9 deacetylase activity / protein delipidation / regulation of lipid catabolic process / NAD+- protein-lysine ADP-ribosyltransferase activity / chromosome, subtelomeric region / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity ...NAD-dependent histone H3K56 deacetylase activity / NAD-dependent histone H3K18 deacetylase activity / ketone biosynthetic process / NAD-dependent histone H3K9 deacetylase activity / protein delipidation / regulation of lipid catabolic process / NAD+- protein-lysine ADP-ribosyltransferase activity / chromosome, subtelomeric region / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / NAD+-protein-arginine ADP-ribosyltransferase activity / positive regulation of protein localization to chromatin / DNA damage sensor activity / positive regulation of stem cell differentiation / positive regulation of blood vessel branching / NAD-dependent protein lysine deacetylase activity / retrotransposon silencing / protein localization to site of double-strand break / protein acetyllysine N-acetyltransferase / cardiac muscle cell differentiation / positive regulation of chondrocyte proliferation / pericentric heterochromatin formation / positive regulation of telomere maintenance / NAD-dependent histone deacetylase activity / protein deacetylation / negative regulation of glucose import / TORC2 complex binding / lncRNA binding / negative regulation of glycolytic process / negative regulation of protein localization to chromatin / positive regulation of double-strand break repair / DNA repair-dependent chromatin remodeling / positive regulation of vascular endothelial cell proliferation / regulation of double-strand break repair via homologous recombination / negative regulation of protein import into nucleus / negative regulation of gene expression, epigenetic / positive regulation of stem cell population maintenance / positive regulation of stem cell proliferation / regulation of protein secretion / negative regulation of transcription elongation by RNA polymerase II / site of DNA damage / NAD+-protein ADP-ribosyltransferase activity / negative regulation of cellular senescence / regulation of lipid metabolic process / Transferases; Glycosyltransferases; Pentosyltransferases / NAD+ ADP-ribosyltransferase activity / NAD+ binding / subtelomeric heterochromatin formation / positive regulation of fat cell differentiation / negative regulation of gluconeogenesis / nucleosome binding / pericentric heterochromatin / regulation of protein localization to plasma membrane / response to UV / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / nucleotidyltransferase activity / positive regulation of protein export from nucleus / determination of adult lifespan / circadian regulation of gene expression / protein destabilization / base-excision repair / regulation of circadian rhythm / positive regulation of insulin secretion / chromatin DNA binding / Pre-NOTCH Transcription and Translation / transcription corepressor activity / double-strand break repair / positive regulation of fibroblast proliferation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / glucose homeostasis / site of double-strand break / positive regulation of cold-induced thermogenesis / Processing of DNA double-strand break ends / damaged DNA binding / chromatin remodeling / negative regulation of cell population proliferation / intracellular membrane-bounded organelle / chromatin binding / chromatin / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / protein homodimerization activity / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
Sirtuin family / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / DHS-like NAD/FAD-binding domain superfamily
Similarity search - Domain/homology
Chem-AR6 / DI(HYDROXYETHYL)ETHER / : / NAD-dependent protein deacylase sirtuin-6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.88 Å
AuthorsYou, W. / Steegborn, C.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG) Germany
CitationJournal: To Be Published
Title: Development of novel Sirtuin 6 inhibitors and activators based on a protein crystallography-based fragment screen
Authors: You, W. / Steegborn, C.
History
DepositionFeb 23, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 13, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: NAD-dependent protein deacetylase sirtuin-6
B: NAD-dependent protein deacetylase sirtuin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,16721
Polymers67,2632
Non-polymers2,90419
Water3,243180
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4890 Å2
ΔGint-133 kcal/mol
Surface area24600 Å2
Unit cell
Length a, b, c (Å)91.359, 91.359, 142.962
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number173
Space group name H-MP63

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein NAD-dependent protein deacetylase sirtuin-6 / Regulatory protein SIR2 homolog 6 / SIR2-like protein 6


Mass: 33631.594 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT6, SIR2L6 / Plasmid: pET151-D-TOPO / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Rosetta2 pLysS
References: UniProt: Q8N6T7, protein acetyllysine N-acetyltransferase

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Non-polymers , 8 types, 199 molecules

#2: Chemical ChemComp-AR6 / [(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL [HYDROXY-[[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYOXOLAN-2-YL]METHOXY]PHOSPHORYL] HYDROGEN PHOSPHATE / Adenosine-5-Diphosphoribose


Mass: 559.316 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H23N5O14P2
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#7: Chemical ChemComp-V7R / 4-azanyl-~{N}-(4-oxidanylcyclohexyl)benzenesulfonamide


Mass: 270.348 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H18N2O3S / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 180 / 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: 2.61 Å3/Da / Density % sol: 52.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.7
Details: 1.6 M (NH4)2SO4, 10% PEG 400, and Bis-Tris buffer pH 5.7
PH range: 5.7-6.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.3 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 12, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.88→47.65 Å / Num. obs: 109024 / % possible obs: 99.7 % / Redundancy: 5.5 % / Biso Wilson estimate: 38.737 Å2 / CC1/2: 0.995 / Rrim(I) all: 0.16 / Net I/σ(I): 7.56
Reflection shellResolution: 1.88→1.99 Å / Mean I/σ(I) obs: 0.72 / Num. unique obs: 17490 / CC1/2: 0.365 / Rrim(I) all: 2.81

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.88→45.68 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.955 / Cross valid method: THROUGHOUT / ESU R: 0.029 / ESU R Free: 0.027 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22691 1073 1.9 %RANDOM
Rwork0.19319 ---
obs0.19382 54044 99.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 39.452 Å2
Baniso -1Baniso -2Baniso -3
1--18.37 Å2-0 Å2-0 Å2
2---18.37 Å2-0 Å2
3---36.75 Å2
Refinement stepCycle: 1 / Resolution: 1.88→45.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4360 0 170 180 4710
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0134619
X-RAY DIFFRACTIONr_bond_other_d0.0340.0174399
X-RAY DIFFRACTIONr_angle_refined_deg1.5771.6676278
X-RAY DIFFRACTIONr_angle_other_deg2.2741.59210142
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6825555
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.69719.876242
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.99315764
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.3031549
X-RAY DIFFRACTIONr_chiral_restr0.0770.2594
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.025015
X-RAY DIFFRACTIONr_gen_planes_other0.0120.021025
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_it3.0553.9122232
X-RAY DIFFRACTIONr_mcbond_other3.0553.9092231
X-RAY DIFFRACTIONr_mcangle_it4.1275.8572783
X-RAY DIFFRACTIONr_mcangle_other4.1265.862784
X-RAY DIFFRACTIONr_scbond_it3.4584.372387
X-RAY DIFFRACTIONr_scbond_other3.4574.372388
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.0016.3893496
X-RAY DIFFRACTIONr_long_range_B_refined6.81146.1154901
X-RAY DIFFRACTIONr_long_range_B_other6.8146.1164902
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCSNumber: 2145 / Type: tight thermal / Rms dev position: 4.13 Å / Weight position: 0.5
LS refinement shellResolution: 1.88→1.93 Å
RfactorNum. reflection% reflection
Rfree0.386 83 -
Rwork0.337 3934 -
obs--98.43 %

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