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- PDB-8cno: Improved complex structure of human Sirtuin 6 with its inhibitor ... -

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Basic information

Entry
Database: PDB / ID: 8cno
TitleImproved complex structure of human Sirtuin 6 with its inhibitor cis-resveratrol
ComponentsNAD-dependent protein deacetylase sirtuin-6
KeywordsHYDROLASE / Deacylase / Inhibitor
Function / homology
Function and homology information


histone H3K56 deacetylase activity, NAD-dependent / histone H3K18 deacetylase activity, NAD-dependent / ketone biosynthetic process / histone H3K9 deacetylase activity, hydrolytic mechanism / histone H3K9 deacetylase activity, NAD-dependent / protein delipidation / NAD+-protein-lysine ADP-ribosyltransferase activity / regulation of lipid catabolic process / chromosome, subtelomeric region / positive regulation of protein localization to chromatin ...histone H3K56 deacetylase activity, NAD-dependent / histone H3K18 deacetylase activity, NAD-dependent / ketone biosynthetic process / histone H3K9 deacetylase activity, hydrolytic mechanism / histone H3K9 deacetylase activity, NAD-dependent / protein delipidation / NAD+-protein-lysine ADP-ribosyltransferase activity / regulation of lipid catabolic process / chromosome, subtelomeric region / positive regulation of protein localization to chromatin / NAD+-protein-arginine ADP-ribosyltransferase activity / DNA damage sensor activity / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / positive regulation of stem cell differentiation / negative regulation of D-glucose import / positive regulation of chondrocyte proliferation / transposable element silencing / NAD-dependent protein lysine deacetylase activity / cardiac muscle cell differentiation / protein acetyllysine N-acetyltransferase / pericentric heterochromatin formation / protein deacetylation / histone deacetylase activity, NAD-dependent / protein localization to site of double-strand break / positive regulation of blood vessel branching / negative regulation of glycolytic process / TORC2 complex binding / negative regulation of protein localization to chromatin / positive regulation of vascular endothelial cell proliferation / histone deacetylase regulator activity / negative regulation of protein import into nucleus / regulation of double-strand break repair via homologous recombination / regulation of protein secretion / positive regulation of double-strand break repair / DNA repair-dependent chromatin remodeling / positive regulation of stem cell proliferation / lncRNA binding / negative regulation of gene expression, epigenetic / NAD+-protein mono-ADP-ribosyltransferase activity / positive regulation of stem cell population maintenance / positive regulation of telomere maintenance / regulation of lipid metabolic process / site of DNA damage / negative regulation of cellular senescence / negative regulation of transcription elongation by RNA polymerase II / Transferases; Glycosyltransferases; Pentosyltransferases / NAD+ poly-ADP-ribosyltransferase activity / NAD+ binding / negative regulation of gluconeogenesis / positive regulation of fat cell differentiation / subtelomeric heterochromatin formation / pericentric heterochromatin / response to UV / regulation of protein localization to plasma membrane / nucleosome binding / enzyme regulator activity / 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 / base-excision repair / regulation of circadian rhythm / positive regulation of insulin secretion / protein destabilization / chromatin DNA binding / Pre-NOTCH Transcription and Translation / positive regulation of fibroblast proliferation / protein import into nucleus / transcription corepressor activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / glucose homeostasis / double-strand break repair / 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 / endoplasmic reticulum / negative regulation of transcription by RNA polymerase II / protein homodimerization activity / DNA binding / 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 / TRIETHYLENE GLYCOL / RESVERATROL / NAD-dependent protein deacylase sirtuin-6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 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 6, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)70,62128
Polymers67,2632
Non-polymers3,35826
Water3,099172
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7790 Å2
ΔGint-177 kcal/mol
Surface area24140 Å2
Unit cell
Length a, b, c (Å)91.276, 91.276, 143.230
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 , 10 types, 198 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-STL / RESVERATROL


Mass: 228.243 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H12O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: SO4
#8: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Cl
#9: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#10: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 172 / 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: 52.9 %
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: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 14, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.75→47.74 Å / Num. obs: 67988 / % possible obs: 99.9 % / Redundancy: 10.2 % / Biso Wilson estimate: 35.441 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.12 / Net I/σ(I): 12.9
Reflection shellResolution: 1.75→1.86 Å / Mean I/σ(I) obs: 1.18 / Num. unique obs: 10915 / CC1/2: 0.421 / Rrim(I) all: 2.11 / % possible all: 99.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→45.64 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.967 / Cross valid method: THROUGHOUT / ESU R: 0.02 / ESU R Free: 0.019 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.18761 2069 3 %RANDOM
Rwork0.1666 ---
obs0.16725 65918 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 33.955 Å2
Baniso -1Baniso -2Baniso -3
1--9.14 Å2-0 Å2-0 Å2
2---9.14 Å2-0 Å2
3---18.27 Å2
Refinement stepCycle: 1 / Resolution: 1.75→45.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4364 0 197 172 4733
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0134643
X-RAY DIFFRACTIONr_bond_other_d0.0340.0174414
X-RAY DIFFRACTIONr_angle_refined_deg1.6491.6666299
X-RAY DIFFRACTIONr_angle_other_deg2.2941.58610173
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8335555
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.56919.918243
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.39515766
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.9421549
X-RAY DIFFRACTIONr_chiral_restr0.080.2590
X-RAY DIFFRACTIONr_gen_planes_refined0.010.025041
X-RAY DIFFRACTIONr_gen_planes_other0.0180.021031
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_it2.9683.3332232
X-RAY DIFFRACTIONr_mcbond_other2.9673.332231
X-RAY DIFFRACTIONr_mcangle_it3.934.9952783
X-RAY DIFFRACTIONr_mcangle_other3.9314.9972784
X-RAY DIFFRACTIONr_scbond_it3.383.7762411
X-RAY DIFFRACTIONr_scbond_other3.3433.752376
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.8075.4593463
X-RAY DIFFRACTIONr_long_range_B_refined6.5839.0484883
X-RAY DIFFRACTIONr_long_range_B_other6.54938.9844861
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCSNumber: 2149 / Type: tight thermal / Rms dev position: 3.87 Å / Weight position: 0.5
LS refinement shellResolution: 1.75→1.794 Å
RfactorNum. reflection% reflection
Rfree0.315 157 -
Rwork0.26 4795 -
obs--98.8 %

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