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- PDB-6xvg: Human Sirt6 3-318 in complex with ADP-ribose and the activator MDL-801 -

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Basic information

Entry
Database: PDB / ID: 6xvg
TitleHuman Sirt6 3-318 in complex with ADP-ribose and the activator MDL-801
ComponentsNAD-dependent protein deacetylase sirtuin-6
KeywordsHYDROLASE / Deacylase / Activator / Allosteric / Isoform-selective
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 / regulation of protein localization to plasma membrane / pericentric heterochromatin / nucleosome binding / negative regulation of gluconeogenesis / 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-8L9 / Chem-AR6 / NAD-dependent protein deacylase sirtuin-6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsYou, W. / Steegborn, C.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)STE1701/15 Germany
CitationJournal: Nat.Chem.Biol. / Year: 2021
Title: Binding site for activator MDL-801 on SIRT6.
Authors: You, W. / Steegborn, C.
History
DepositionJan 22, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 28, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 17, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2May 5, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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
C: NAD-dependent protein deacetylase sirtuin-6
D: NAD-dependent protein deacetylase sirtuin-6
E: NAD-dependent protein deacetylase sirtuin-6
F: NAD-dependent protein deacetylase sirtuin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)219,42645
Polymers210,0196
Non-polymers9,40839
Water3,045169
1
A: NAD-dependent protein deacetylase sirtuin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4286
Polymers35,0031
Non-polymers1,4255
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: NAD-dependent protein deacetylase sirtuin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,81310
Polymers35,0031
Non-polymers1,8099
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: NAD-dependent protein deacetylase sirtuin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6128
Polymers35,0031
Non-polymers1,6097
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: NAD-dependent protein deacetylase sirtuin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6208
Polymers35,0031
Non-polymers1,6177
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
E: NAD-dependent protein deacetylase sirtuin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7129
Polymers35,0031
Non-polymers1,7098
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
F: NAD-dependent protein deacetylase sirtuin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2404
Polymers35,0031
Non-polymers1,2373
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)89.510, 136.534, 89.873
Angle α, β, γ (deg.)90.000, 117.710, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14A
24E
15A
25F
16B
26C
17B
27D
18B
28E
19B
29F
110C
210D
111C
211E
112C
212F
113D
213E
114D
214F
115E
215F

NCS domain segments:

Component-ID: 0 / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LYSLYSGLUGLUAA15 - 29813 - 296
21LYSLYSGLUGLUBB15 - 29813 - 296
12ASPASPGLUGLUAA14 - 29812 - 296
22ASPASPGLUGLUCC14 - 29812 - 296
13LYSLYSLEULEUAA15 - 29713 - 295
23LYSLYSLEULEUDD15 - 29713 - 295
14ASPASPLEULEUAA14 - 29712 - 295
24ASPASPLEULEUEE14 - 29712 - 295
15ASPASPGLUGLUAA14 - 29812 - 296
25ASPASPGLUGLUFF14 - 29812 - 296
16LYSLYSGLUGLUBB15 - 29813 - 296
26LYSLYSGLUGLUCC15 - 29813 - 296
17LYSLYSGLUGLUBB15 - 29813 - 296
27LYSLYSGLUGLUDD15 - 29813 - 296
18LYSLYSGLUGLUBB15 - 29813 - 296
28LYSLYSGLUGLUEE15 - 29813 - 296
19LYSLYSGLUGLUBB15 - 29813 - 296
29LYSLYSGLUGLUFF15 - 29813 - 296
110LYSLYSGLUGLUCC15 - 29813 - 296
210LYSLYSGLUGLUDD15 - 29813 - 296
111ASPASPGLUGLUCC14 - 29812 - 296
211ASPASPGLUGLUEE14 - 29812 - 296
112ASPASPGLUGLUCC14 - 29812 - 296
212ASPASPGLUGLUFF14 - 29812 - 296
113LYSLYSLEULEUDD15 - 29713 - 295
213LYSLYSLEULEUEE15 - 29713 - 295
114LYSLYSLEULEUDD15 - 29713 - 295
214LYSLYSLEULEUFF15 - 29713 - 295
115ASPASPLEULEUEE14 - 29712 - 295
215ASPASPLEULEUFF14 - 29712 - 295

NCS ensembles :
ID
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

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Components

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Protein , 1 types, 6 molecules ABCDEF

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


Mass: 35003.105 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT6, SIR2L6 / Plasmid: pET28a-SUMO / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): codon+
References: UniProt: Q8N6T7, protein acetyllysine N-acetyltransferase

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Non-polymers , 6 types, 208 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.: 6 / Source method: obtained synthetically / Formula: C15H23N5O14P2
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical
ChemComp-8L9 / 5-[[3,5-bis(chloranyl)phenyl]sulfonylamino]-2-[(5-bromanyl-4-fluoranyl-2-methyl-phenyl)sulfamoyl]benzoic acid


Mass: 612.273 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C20H14BrCl2FN2O6S2 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 169 / 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: 2.38 Å3/Da / Density % sol: 48.42 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 85 mM HEPES pH 7.5, 85 mM sodium chloride, 1.36 M (NH4)2SO4, 15% glycerol
PH range: 7.0-7.7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Nov 7, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.1→46.39 Å / Num. obs: 110958 / % possible obs: 99.4 % / Redundancy: 14 % / Biso Wilson estimate: 51.46 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.13 / Net I/σ(I): 15.7
Reflection shellResolution: 2.1→2.23 Å / Redundancy: 14.3 % / Mean I/σ(I) obs: 1.1 / Num. unique obs: 17501 / CC1/2: 0.499 / Rrim(I) all: 2.4 / % possible all: 97.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3K35

3k35


Resolution: 2.1→46.39 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.948 / SU B: 7.147 / SU ML: 0.172 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.217 / ESU R Free: 0.172 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2298 2101 1.9 %RANDOM
Rwork0.2044 ---
obs0.2049 108840 99.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 193.34 Å2 / Biso mean: 53.293 Å2 / Biso min: 29.57 Å2
Baniso -1Baniso -2Baniso -3
1--2.55 Å20 Å2-0.48 Å2
2--1.69 Å20 Å2
3---0.88 Å2
Refinement stepCycle: final / Resolution: 2.1→46.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12939 0 539 169 13647
Biso mean--82.5 43.42 -
Num. residues----1675
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.01313765
X-RAY DIFFRACTIONr_bond_other_d0.0030.01712668
X-RAY DIFFRACTIONr_angle_refined_deg1.4841.67618771
X-RAY DIFFRACTIONr_angle_other_deg1.3221.57829320
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.18551664
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.39820.213703
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.657152214
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5515136
X-RAY DIFFRACTIONr_chiral_restr0.0690.21764
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0215082
X-RAY DIFFRACTIONr_gen_planes_other0.0090.022812
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A83750.09
12B83750.09
21A84700.07
22C84700.07
31A84230.07
32D84230.07
41A83620.08
42E83620.08
51A84680.08
52F84680.08
61B83060.08
62C83060.08
71B83850.08
72D83850.08
81B83610.08
82E83610.08
91B83940.07
92F83940.07
101C83760.08
102D83760.08
111C83860.08
112E83860.08
121C84160.08
122F84160.08
131D83660.07
132E83660.07
141D83700.07
142F83700.07
151E83440.08
152F83440.08
LS refinement shellResolution: 2.1→2.153 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.403 147 -
Rwork0.363 7619 -
obs--94.87 %

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