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- PDB-5y2f: Human SIRT6 in complex with allosteric activator MDL-801 -

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Basic information

Entry
Database: PDB / ID: 5y2f
TitleHuman SIRT6 in complex with allosteric activator MDL-801
Components
  • 9-mer peptide QTARKSTGG
  • NAD-dependent protein deacetylase sirtuin-6
KeywordsHYDROLASE/PEPTIDE / agnonist / complex / sirt6 / HYDROLASE-PEPTIDE complex
Function / homology
Function and homology information


NAD-dependent histone H3K56 deacetylase activity / NAD-dependent histone H3K18 deacetylase activity / NAD-dependent histone H3K9 deacetylase activity / protein delipidation / ketone biosynthetic process / 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 / NAD-dependent histone H3K9 deacetylase activity / protein delipidation / ketone biosynthetic process / 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 acetyllysine N-acetyltransferase / cardiac muscle cell differentiation / positive regulation of chondrocyte proliferation / pericentric heterochromatin formation / positive regulation of telomere maintenance / protein deacetylation / negative regulation of glucose import / protein localization to site of double-strand break / NAD-dependent histone deacetylase activity / 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 / negative regulation of protein import into nucleus / negative regulation of gene expression, epigenetic / regulation of double-strand break repair via homologous recombination / 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 / NAD+-protein ADP-ribosyltransferase activity / negative regulation of cellular senescence / site of DNA damage / 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 / Chromatin modifying enzymes / negative regulation of gluconeogenesis / epigenetic regulation of gene expression / response to UV / nucleosome binding / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / telomere organization / RNA Polymerase I Promoter Opening / Interleukin-7 signaling / nucleotidyltransferase activity / Assembly of the ORC complex at the origin of replication / DNA methylation / Condensation of Prophase Chromosomes / positive regulation of protein export from nucleus / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / SIRT1 negatively regulates rRNA expression / Chromatin modifications during the maternal to zygotic transition (MZT) / HCMV Late Events / PRC2 methylates histones and DNA / Defective pyroptosis / HDACs deacetylate histones / determination of adult lifespan / RNA Polymerase I Promoter Escape / Transcriptional regulation by small RNAs / Formation of the beta-catenin:TCF transactivating complex / circadian regulation of gene expression / protein destabilization / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / NoRC negatively regulates rRNA expression / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / base-excision repair / B-WICH complex positively regulates rRNA expression / HDMs demethylate histones / regulation of circadian rhythm / positive regulation of insulin secretion / chromatin DNA binding / PKMTs methylate histone lysines / Meiotic recombination / RMTs methylate histone arginines / Pre-NOTCH Transcription and Translation / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / Transcriptional regulation of granulopoiesis / structural constituent of chromatin / transcription corepressor activity / nucleosome / positive regulation of fibroblast proliferation / double-strand break repair / nucleosome assembly
Similarity search - Function
Rubrerythrin, domain 2 - #200 / Sirtuin family / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / TPP-binding domain / Rubrerythrin, domain 2 / DHS-like NAD/FAD-binding domain superfamily / Single Sheet / Histone H3 signature 1. ...Rubrerythrin, domain 2 - #200 / Sirtuin family / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / TPP-binding domain / Rubrerythrin, domain 2 / DHS-like NAD/FAD-binding domain superfamily / Single Sheet / Histone H3 signature 1. / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Histone-fold / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Chem-8L9 / Chem-AR6 / HEXADECANE-1-SULFINIC ACID / DI(HYDROXYETHYL)ETHER / Histone H3.1 / NAD-dependent protein deacylase sirtuin-6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.53 Å
AuthorsZhang, J. / Huang, Z. / Song, K.
CitationJournal: Nat. Chem. Biol. / Year: 2018
Title: Identification of a cellularly active SIRT6 allosteric activator.
Authors: Huang, Z. / Zhao, J. / Deng, W. / Chen, Y. / Shang, J. / Song, K. / Zhang, L. / Wang, C. / Lu, S. / Yang, X. / He, B. / Min, J. / Hu, H. / Tan, M. / Xu, J. / Zhang, Q. / Zhong, J. / Sun, X. ...Authors: Huang, Z. / Zhao, J. / Deng, W. / Chen, Y. / Shang, J. / Song, K. / Zhang, L. / Wang, C. / Lu, S. / Yang, X. / He, B. / Min, J. / Hu, H. / Tan, M. / Xu, J. / Zhang, Q. / Zhong, J. / Sun, X. / Mao, Z. / Lin, H. / Xiao, M. / Chin, Y.E. / Jiang, H. / Xu, Y. / Chen, G. / Zhang, J.
History
DepositionJul 25, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 7, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 14, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed ..._citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Nov 28, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: NAD-dependent protein deacetylase sirtuin-6
C: 9-mer peptide QTARKSTGG
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,67719
Polymers35,9102
Non-polymers2,76717
Water2,378132
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4390 Å2
ΔGint-81 kcal/mol
Surface area14750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)162.422, 162.422, 162.422
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number213
Space group name H-MP4132

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AC

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


Mass: 35003.105 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 3-318
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT6, SIR2L6 / Production host: Escherichia coli (E. coli)
References: UniProt: Q8N6T7, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides
#2: Protein/peptide 9-mer peptide QTARKSTGG


Mass: 906.984 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P68431*PLUS

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Non-polymers , 8 types, 149 molecules

#3: 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


Mass: 559.316 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H23N5O14P2
#4: 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.: 1 / Source method: obtained synthetically / Formula: C20H14BrCl2FN2O6S2
#5: Chemical ChemComp-ZN / ZINC ION


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


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#8: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#9: Chemical ChemComp-HDR / HEXADECANE-1-SULFINIC ACID


Mass: 290.505 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H34O2S
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 132 / Source method: isolated from a natural source / Formula: H2O

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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: 4.97 Å3/Da / Density % sol: 72.47 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.2 M (NH4)2SO4, 0.1 M Mes pH 6.5, 20% W/v PEG 8000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97857 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Aug 6, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 2.53→114.85 Å / Num. obs: 24828 / % possible obs: 98.7 % / Redundancy: 42.7 % / Rmerge(I) obs: 0.137 / Net I/σ(I): 30.8
Reflection shellResolution: 2.53→2.66 Å / Redundancy: 41.9 % / Num. unique obs: 3578 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
HKL-3000data processing
Aimlessdata scaling
PHASERphasing
RefinementResolution: 2.53→114.85 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.934 / SU B: 6.575 / SU ML: 0.138 / Cross valid method: THROUGHOUT / ESU R: 0.206 / ESU R Free: 0.189 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21664 1261 5.1 %RANDOM
Rwork0.17505 ---
obs0.17724 23520 98.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 69.863 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: 1 / Resolution: 2.53→115.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2368 0 158 132 2658
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0192584
X-RAY DIFFRACTIONr_bond_other_d0.0020.022473
X-RAY DIFFRACTIONr_angle_refined_deg1.5762.0383502
X-RAY DIFFRACTIONr_angle_other_deg0.993.0015689
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8465305
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.34722105
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.92415417
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.6811529
X-RAY DIFFRACTIONr_chiral_restr0.0810.2387
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212771
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02563
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_it4.4016.4921223
X-RAY DIFFRACTIONr_mcbond_other4.4016.4861222
X-RAY DIFFRACTIONr_mcangle_it6.9589.711527
X-RAY DIFFRACTIONr_mcangle_other6.9589.7161528
X-RAY DIFFRACTIONr_scbond_it5.2177.5441359
X-RAY DIFFRACTIONr_scbond_other5.2127.5451359
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other8.34411.0781976
X-RAY DIFFRACTIONr_long_range_B_refined12.94153.9052769
X-RAY DIFFRACTIONr_long_range_B_other13.00553.8952738
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.528→2.593 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.358 83 -
Rwork0.325 1734 -
obs--100 %

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