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- PDB-8i2b: Human SIRT6 in complex with inhibitor 7702 -

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Basic information

Entry
Database: PDB / ID: 8i2b
TitleHuman SIRT6 in complex with inhibitor 7702
ComponentsNAD-dependent protein deacylase sirtuin-6
KeywordsLYASE/INHIBITOR / LYASE-INHIBITOR COMPLEX
Function / homology
Function and homology information


histone H3K56 deacetylase activity, NAD-dependent / histone H3K4 deacetylase activity, NAD-dependent / ketone biosynthetic process / histone H3K18 deacetylase activity, NAD-dependent / histone H3K14 deacetylase activity, NAD-dependent / histone H3K9 deacetylase activity, NAD-dependent / protein delipidation / NAD+-protein-lysine ADP-ribosyltransferase activity / regulation of lipid catabolic process / chromosome, subtelomeric region ...histone H3K56 deacetylase activity, NAD-dependent / histone H3K4 deacetylase activity, NAD-dependent / ketone biosynthetic process / histone H3K18 deacetylase activity, NAD-dependent / histone H3K14 deacetylase activity, NAD-dependent / 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-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / NAD+-protein-arginine ADP-ribosyltransferase activity / DNA damage sensor activity / histone H3K9 deacetylase activity, hydrolytic mechanism / histone H4K16 deacetylase activity, NAD-dependent / positive regulation of stem cell differentiation / negative regulation of D-glucose import / NAD-dependent protein lysine deacetylase activity / positive regulation of chondrocyte proliferation / transposable element silencing / protein acetyllysine N-acetyltransferase / cardiac muscle cell differentiation / 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 / negative regulation of protein localization to chromatin / TORC2 complex binding / positive regulation of vascular endothelial cell proliferation / histone deacetylase regulator activity / regulation of double-strand break repair via homologous recombination / positive regulation of double-strand break repair / negative regulation of protein import into nucleus / regulation of protein secretion / DNA repair-dependent chromatin remodeling / lncRNA binding / negative regulation of gene expression, epigenetic / positive regulation of stem cell proliferation / positive regulation of stem cell population maintenance / NAD+-protein mono-ADP-ribosyltransferase activity / positive regulation of telomere maintenance / site of DNA damage / regulation of lipid metabolic process / NAD+ poly-ADP-ribosyltransferase activity / negative regulation of transcription elongation by RNA polymerase II / negative regulation of cellular senescence / Transferases; Glycosyltransferases; Pentosyltransferases / 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 / positive regulation of insulin secretion / base-excision repair / 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 / 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 / Chem-O5L / NAD-dependent protein deacylase sirtuin-6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsWang, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)21977121 China
CitationJournal: Acta Pharm Sin B / Year: 2024
Title: Discovery of a potent and highly selective inhibitor of SIRT6 against pancreatic cancer metastasis in vivo.
Authors: Xu, X. / Zhang, Q. / Wang, X. / Jin, J. / Wu, C. / Feng, L. / Yang, X. / Zhao, M. / Chen, Y. / Lu, S. / Zheng, Z. / Lan, X. / Wang, Y. / Zheng, Y. / Lu, X. / Zhang, Q. / Zhang, J.
History
DepositionJan 14, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 17, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 30, 2025Group: Database references / Derived calculations / Structure summary
Category: chem_comp / citation ...chem_comp / citation / citation_author / entity / pdbx_entity_nonpoly / pdbx_entry_details
Item: _chem_comp.name / _citation.country ..._chem_comp.name / _citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _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 deacylase sirtuin-6
B: NAD-dependent protein deacylase sirtuin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,76216
Polymers64,5262
Non-polymers3,23514
Water1,38777
1
A: NAD-dependent protein deacylase sirtuin-6
B: NAD-dependent protein deacylase sirtuin-6
hetero molecules

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

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


Theoretical massNumber of molelcules
Total (without water)203,28548
Polymers193,5796
Non-polymers9,70642
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 area22680 Å2
ΔGint-256 kcal/mol
Surface area67230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.318, 91.318, 143.674
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number173
Space group name H-MP63
Components on special symmetry positions
IDModelComponents
11B-725-

HOH

21B-737-

HOH

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein NAD-dependent protein deacylase sirtuin-6 / NAD-dependent protein deacetylase sirtuin-6 / Protein mono-ADP-ribosyltransferase sirtuin-6 / ...NAD-dependent protein deacetylase sirtuin-6 / Protein mono-ADP-ribosyltransferase sirtuin-6 / Regulatory protein SIR2 homolog 6 / hSIRT6 / SIR2-like protein 6


Mass: 32263.111 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT6 / Production host: Escherichia phage EcSzw-2 (virus)
References: UniProt: Q8N6T7, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups, protein acetyllysine N-acetyltransferase

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Non-polymers , 6 types, 91 molecules

#2: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#3: Chemical ChemComp-O5L / N1-[[4-(4-aminophenyl)sulfanyl-3-(trifluoromethyl)phenyl]methoxy]benzene-1,4-dicarboxamide


Mass: 461.457 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H18F3N3O3S / Feature type: SUBJECT OF INVESTIGATION
#4: 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
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#6: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 77 / 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: 2.76 Å3/Da / Density % sol: 55.48 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: 0.1M Bis-tris pH 5.7, 1.6 M (NH4)2SO4, 10% PEG400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL10U2 / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER2 S 16M / Detector: PIXEL / Date: Oct 17, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.2→40.97 Å / Num. obs: 34506 / % possible obs: 99.9 % / Redundancy: 19.17 % / CC1/2: 0.99 / Net I/σ(I): 15.35
Reflection shellResolution: 2.2→2.279 Å / Num. unique obs: 5567 / CC1/2: 0.965

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Processing

Software
NameVersionClassification
REFMACCCP4 Interface 7.1.010refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→40.97 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.931 / SU B: 3.496 / SU ML: 0.098 / Cross valid method: THROUGHOUT / ESU R: 0.053 / ESU R Free: 0.043 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23751 1735 5 %RANDOM
Rwork0.19223 ---
obs0.19442 32687 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: 47.79 Å2
Baniso -1Baniso -2Baniso -3
1-0.02 Å20 Å20 Å2
2--0.02 Å20 Å2
3----0.03 Å2
Refinement stepCycle: 1 / Resolution: 2.2→40.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4392 0 202 77 4671
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0134690
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174460
X-RAY DIFFRACTIONr_angle_refined_deg1.5981.6566366
X-RAY DIFFRACTIONr_angle_other_deg1.2921.58310278
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.045558
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.10919.839249
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.45515772
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.8471550
X-RAY DIFFRACTIONr_chiral_restr0.0790.2595
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.025114
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021052
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_it4.5194.6662244
X-RAY DIFFRACTIONr_mcbond_other4.5174.6642243
X-RAY DIFFRACTIONr_mcangle_it5.8456.972797
X-RAY DIFFRACTIONr_mcangle_other5.8456.9732798
X-RAY DIFFRACTIONr_scbond_it5.2155.3922446
X-RAY DIFFRACTIONr_scbond_other5.185.3662427
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.3647.8193539
X-RAY DIFFRACTIONr_long_range_B_refined11.03789.43918728
X-RAY DIFFRACTIONr_long_range_B_other11.04389.4218702
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 8467 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.08 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.15 128 -
Rwork0.1 2398 -
obs--99.53 %

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