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- PDB-9g7h: Human Sirt6 in complex with ADP-ribose and the inhibitor 2-Pr -

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Basic information

Entry
Database: PDB / ID: 9g7h
TitleHuman Sirt6 in complex with ADP-ribose and the inhibitor 2-Pr
ComponentsNAD-dependent protein deacetylase sirtuin-6
KeywordsGENE REGULATION / Deacylase / inhibitor / DNA-Encoded Chemical Libraries / Acyl binding pocket / Aging
Function / homology
Function and homology information


ketone biosynthetic process / protein delipidation / NAD+-protein-lysine ADP-ribosyltransferase activity / regulation of lipid catabolic process / chromosome, subtelomeric region / positive regulation of protein localization to chromatin / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / NAD+-protein-arginine ADP-ribosyltransferase activity / DNA damage sensor activity ...ketone biosynthetic process / protein delipidation / NAD+-protein-lysine ADP-ribosyltransferase activity / regulation of lipid catabolic process / chromosome, subtelomeric region / positive regulation of protein localization to chromatin / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / NAD+-protein-arginine ADP-ribosyltransferase activity / DNA damage sensor activity / positive regulation of stem cell differentiation / NAD-dependent protein lysine deacetylase activity / positive regulation of chondrocyte proliferation / transposable element silencing / cardiac muscle cell differentiation / protein acetyllysine N-acetyltransferase / histone H3K14 deacetylase activity, NAD-dependent / histone H3K9 deacetylase activity, NAD-dependent / histone H4K16 deacetylase activity, NAD-dependent / histone H3K18 deacetylase activity, NAD-dependent / histone H3K56 deacetylase activity, NAD-dependent / histone H3K4 deacetylase activity, NAD-dependent / pericentric heterochromatin formation / histone deacetylase activity, NAD-dependent / protein deacetylation / negative regulation of D-glucose import / protein localization to site of double-strand break / positive regulation of blood vessel branching / histone H3K9 deacetylase activity, hydrolytic mechanism / negative regulation of glycolytic process / negative regulation of protein localization to chromatin / positive regulation of vascular endothelial cell proliferation / TORC2 complex binding / histone deacetylase regulator activity / regulation of double-strand break repair via homologous recombination / negative regulation of protein import into nucleus / positive regulation of double-strand break repair / lncRNA binding / regulation of protein secretion / DNA repair-dependent chromatin remodeling / positive regulation of stem cell proliferation / negative regulation of gene expression, epigenetic / positive regulation of stem cell population maintenance / NAD+-protein mono-ADP-ribosyltransferase activity / positive regulation of telomere maintenance / negative regulation of transcription elongation by RNA polymerase II / site of DNA damage / regulation of lipid metabolic process / NAD+ poly-ADP-ribosyltransferase activity / Transferases; Glycosyltransferases; Pentosyltransferases / negative regulation of cellular senescence / NAD+ binding / positive regulation of fat cell differentiation / negative regulation of gluconeogenesis / subtelomeric heterochromatin formation / pericentric heterochromatin / regulation of protein localization to plasma membrane / response to UV / 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 / regulation of circadian rhythm / protein destabilization / base-excision repair / positive regulation of insulin secretion / chromatin DNA binding / Pre-NOTCH Transcription and Translation / positive regulation of fibroblast proliferation / protein import into nucleus / transcription corepressor activity / glucose homeostasis / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / 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 / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / 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 / 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 support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Chemmedchem / Year: 2024
Title: Elucidating the Unconventional Binding Mode of a DNA-Encoded Library Hit Provides a Blueprint for Sirtuin 6 Inhibitor Development.
Authors: You, W. / Montoya, A.L. / Dana, S. / Franzini, R.M. / Steegborn, C.
History
DepositionJul 21, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 14, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.journal_volume / _citation_author.identifier_ORCID / _pdbx_entry_details.has_protein_modification

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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)69,72714
Polymers67,2632
Non-polymers2,46312
Water2,666148
1
A: NAD-dependent protein deacetylase sirtuin-6
B: NAD-dependent protein deacetylase sirtuin-6
hetero molecules

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

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


Theoretical massNumber of molelcules
Total (without water)209,18042
Polymers201,7906
Non-polymers7,39036
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-y,x-y,z1
crystal symmetry operation3_555-x+y,-x,z1
Buried area19500 Å2
ΔGint-348 kcal/mol
Surface area65750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.466, 91.466, 144.608
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 (E. coli) / Variant (production host): Rosetta2 (DE3) pLysS
References: UniProt: Q8N6T7, protein acetyllysine N-acetyltransferase

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Non-polymers , 5 types, 160 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: isolated from a natural source / Formula: Zn
#4: Chemical ChemComp-A1IIZ / 2,4-bis(oxidanylidene)-1-[2-oxidanylidene-2-[[(2S)-3-oxidanylidene-3-(propylamino)-2-[3-(3-pyridin-3-yl-1,2,4-oxadiazol-5-yl)propanoylamino]propyl]amino]ethyl]pyrimidine-5-carboxamide


Mass: 541.517 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H27N9O7 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 148 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.73 Å3/Da / Density % sol: 54.95 %
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: Oct 13, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.75→45.73 Å / Num. obs: 68965 / % possible obs: 100 % / Redundancy: 9.5 % / Biso Wilson estimate: 38.224 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.13 / Net I/σ(I): 12.39
Reflection shellResolution: 1.75→1.86 Å / Redundancy: 9.2 % / Mean I/σ(I) obs: 0.89 / Num. unique obs: 11124 / CC1/2: 0.349 / Rrim(I) all: 2.63 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→45.73 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.955 / SU B: 1.366 / SU ML: 0.048 / Cross valid method: THROUGHOUT / ESU R: 0.02 / ESU R Free: 0.02 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20185 2149 3.1 %RANDOM
Rwork0.16741 ---
obs0.16845 66815 99.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 37.489 Å2
Baniso -1Baniso -2Baniso -3
1--12.04 Å2-0 Å2-0 Å2
2---12.04 Å2-0 Å2
3---24.08 Å2
Refinement stepCycle: 1 / Resolution: 1.75→45.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4360 0 148 148 4656
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0124603
X-RAY DIFFRACTIONr_bond_other_d0.0020.0164368
X-RAY DIFFRACTIONr_angle_refined_deg1.9111.8656261
X-RAY DIFFRACTIONr_angle_other_deg0.7021.78310069
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7565555
X-RAY DIFFRACTIONr_dihedral_angle_2_deg11.819549
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.95310764
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0930.2708
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.025374
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021023
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_it3.8913.6682232
X-RAY DIFFRACTIONr_mcbond_other3.8913.6682232
X-RAY DIFFRACTIONr_mcangle_it4.9326.6022783
X-RAY DIFFRACTIONr_mcangle_other4.9336.6042784
X-RAY DIFFRACTIONr_scbond_it4.2374.0752371
X-RAY DIFFRACTIONr_scbond_other4.2154.0632344
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.8117.2993437
X-RAY DIFFRACTIONr_long_range_B_refined7.39835.854751
X-RAY DIFFRACTIONr_long_range_B_other7.39535.834740
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.75→1.794 Å
RfactorNum. reflection% reflection
Rfree0.316 151 -
Rwork0.253 4928 -
obs--99.8 %

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