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- PDB-6nr0: SIRT2(56-356) with covalent intermediate between mechanism-based ... -

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Basic information

Entry
Database: PDB / ID: 6nr0
TitleSIRT2(56-356) with covalent intermediate between mechanism-based inhibitor Glucose-TM-1beta and 1'-SH ADP-ribose
ComponentsNAD-dependent protein deacetylase sirtuin-2
Keywordshydrolase/hydrolase inhibitor / inhibitor / intermediate / deacylase / HYDROLASE / hydrolase-hydrolase inhibitor complex
Function / homology
Function and homology information


cellular response to caloric restriction / negative regulation of oligodendrocyte progenitor proliferation / negative regulation of striated muscle tissue development / negative regulation of satellite cell differentiation / positive regulation of attachment of spindle microtubules to kinetochore / positive regulation of meiotic nuclear division / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / paranodal junction / peptidyl-lysine deacetylation ...cellular response to caloric restriction / negative regulation of oligodendrocyte progenitor proliferation / negative regulation of striated muscle tissue development / negative regulation of satellite cell differentiation / positive regulation of attachment of spindle microtubules to kinetochore / positive regulation of meiotic nuclear division / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / paranodal junction / peptidyl-lysine deacetylation / tubulin deacetylation / lateral loop / NLRP3 inflammasome complex assembly / negative regulation of NLRP3 inflammasome complex assembly / mitotic nuclear membrane reassembly / tubulin deacetylase activity / regulation of exit from mitosis / paranode region of axon / Schmidt-Lanterman incisure / positive regulation of fatty acid biosynthetic process / NAD-dependent protein lysine deacetylase activity / 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 / negative regulation of peptidyl-threonine phosphorylation / myelination in peripheral nervous system / rDNA heterochromatin formation / histone deacetylase activity, NAD-dependent / regulation of phosphorylation / protein deacetylation / positive regulation of oocyte maturation / Initiation of Nuclear Envelope (NE) Reformation / juxtaparanode region of axon / chromatin silencing complex / meiotic spindle / protein lysine deacetylase activity / response to redox state / regulation of myelination / positive regulation of DNA binding / histone deacetylase activity / histone acetyltransferase binding / negative regulation of fat cell differentiation / negative regulation of reactive oxygen species metabolic process / NAD+ poly-ADP-ribosyltransferase activity / positive regulation of execution phase of apoptosis / positive regulation of cell division / NAD+ binding / glial cell projection / subtelomeric heterochromatin formation / heterochromatin / lipid catabolic process / cellular response to epinephrine stimulus / substantia nigra development / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / centriole / negative regulation of autophagy / epigenetic regulation of gene expression / ubiquitin binding / meiotic cell cycle / negative regulation of protein catabolic process / autophagy / spindle / histone deacetylase binding / mitotic spindle / heterochromatin formation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / myelin sheath / chromosome / growth cone / midbody / cellular response to oxidative stress / DNA-binding transcription factor binding / cellular response to hypoxia / perikaryon / microtubule / proteasome-mediated ubiquitin-dependent protein catabolic process / chromosome, telomeric region / regulation of cell cycle / innate immune response / cell division / negative regulation of DNA-templated transcription / centrosome / chromatin binding / nucleolus / perinuclear region of cytoplasm / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / mitochondrion / zinc ion binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Sirtuin, class I / SIR2/SIRT2 'Small Domain' / SIR2/SIRT2 'Small Domain' / Sirtuin, catalytic core small domain superfamily / Sirtuin family / : / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / TPP-binding domain ...Sirtuin, class I / SIR2/SIRT2 'Small Domain' / SIR2/SIRT2 'Small Domain' / Sirtuin, catalytic core small domain superfamily / Sirtuin family / : / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / TPP-binding domain / DHS-like NAD/FAD-binding domain superfamily / Rossmann fold / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-KXG / Chem-KXJ / NAD-dependent protein deacetylase sirtuin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsPrice, I.R. / Hong, J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)1R01DK107868 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM086703-07 United States
CitationJournal: Acs Chem.Biol. / Year: 2019
Title: A Glycoconjugated SIRT2 Inhibitor with Aqueous Solubility Allows Structure-Based Design of SIRT2 Inhibitors.
Authors: Hong, J.Y. / Price, I.R. / Bai, J.J. / Lin, H.
History
DepositionJan 22, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 22, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 27, 2021Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / database_2 / struct_conn / struct_conn_type
Item: _citation.country / _citation.journal_abbrev ..._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 / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn_type.id
Revision 1.2Oct 11, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._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-2
B: NAD-dependent protein deacetylase sirtuin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,38118
Polymers72,3192
Non-polymers3,06216
Water2,414134
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
A: NAD-dependent protein deacetylase sirtuin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,5988
Polymers36,1601
Non-polymers1,4397
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)82.310, 76.840, 114.461
Angle α, β, γ (deg.)90.000, 95.874, 90.000
Int Tables number5
Space group name H-MI121
Space group name HallC2y(x,y,-x+z)
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ARGARGGLNGLN(chain 'A' and (resid 57 through 180 or resid 182...AA57 - 18020 - 143
12ASPASPALAALA(chain 'A' and (resid 57 through 180 or resid 182...AA182 - 290145 - 253
13GLYGLYLYSLYS(chain 'A' and (resid 57 through 180 or resid 182...AA304 - 339267 - 302
14LEULEUGLNGLN(chain 'A' and (resid 57 through 180 or resid 182...AA341 - 355304 - 318
15KXGKXGNANA(chain 'A' and (resid 57 through 180 or resid 182...AE - F403 - 404
26ARGARGGLNGLN(chain 'B' and (resid 57 through 180 or resid 182...BB57 - 18020 - 143
27ASPASPALAALA(chain 'B' and (resid 57 through 180 or resid 182...BB182 - 290145 - 253
28GLYGLYLYSLYS(chain 'B' and (resid 57 through 180 or resid 182...BB304 - 339267 - 302
29LEULEUGLNGLN(chain 'B' and (resid 57 through 180 or resid 182...BB341 - 355304 - 318
210KXGKXGNANA(chain 'B' and (resid 57 through 180 or resid 182...BL - M403 - 404

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein NAD-dependent protein deacetylase sirtuin-2 / Regulatory protein SIR2 homolog 2 / SIR2-like protein 2


Mass: 36159.715 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT2, SIR2L, SIR2L2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: Q8IXJ6, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides

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Non-polymers , 7 types, 150 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-KXJ / N~2~-[3-(2-hydroxyethoxy)propanoyl]-N-phenyl-N~6~-tetradecanethioyl-L-lysinamide


Mass: 563.835 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H53N3O4S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-KXG / [[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(3~{S},4~{R},5~{R})-3,4-bis(oxidanyl)-5-sulfanyl-oxolan-2-yl]methyl hydrogen phosphate


Mass: 575.381 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H23N5O13P2S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: Na
#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#7: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 134 / 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: 2.49 Å3/Da / Density % sol: 55.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5
Details: Mixed solution of 0.44 mM protein (in buffer of 20 mM Tris/HCl pH 7.5, 160 mM NaCl) 2.5 mM NAD+, 2.5 mM Glucose-TM-1beta with an equal volume of well solution of 2 M (NH4)2SO4, 80 mM Na Acetate/HCl pH 5.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9765 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 10, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 2.45→63.693 Å / Num. obs: 25380 / % possible obs: 91.83 % / Redundancy: 2 % / Biso Wilson estimate: 41.82 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.03585 / Rrim(I) all: 0.0507 / Net I/σ(I): 13.33
Reflection shellResolution: 2.45→2.538 Å / Redundancy: 2 % / Rmerge(I) obs: 0.3884 / Mean I/σ(I) obs: 2.06 / Num. unique obs: 2474 / CC1/2: 0.722 / Rrim(I) all: 0.5493 / % possible all: 82.5

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
Cootmodel building
MolProbitymodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4X3O

4x3o


Resolution: 2.45→63.69 Å / SU ML: 0.3557 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 29.1653 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflectionSelection details
Rfree0.2562 1889 7.84 %RANDOM SELECTION
Rwork0.2202 22216 --
obs0.223 24105 91.83 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 51.87 Å2
Refinement stepCycle: LAST / Resolution: 2.45→63.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4615 0 181 134 4930
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01124934
X-RAY DIFFRACTIONf_angle_d1.33966659
X-RAY DIFFRACTIONf_chiral_restr0.2783712
X-RAY DIFFRACTIONf_plane_restr0.0074841
X-RAY DIFFRACTIONf_dihedral_angle_d25.06071881
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.45-2.520.35721250.30151524X-RAY DIFFRACTION82.95
2.52-2.590.39671230.29011524X-RAY DIFFRACTION82.76
2.59-2.670.3251280.2681593X-RAY DIFFRACTION84.49
2.67-2.770.34881380.25371651X-RAY DIFFRACTION89.36
2.77-2.880.28951450.24931645X-RAY DIFFRACTION89.59
2.88-3.010.28371540.25331702X-RAY DIFFRACTION92.66
3.01-3.170.30141550.25141747X-RAY DIFFRACTION94.3
3.17-3.370.30461510.24811764X-RAY DIFFRACTION94.99
3.37-3.630.27381490.22381797X-RAY DIFFRACTION95.67
3.63-3.990.21551510.20551769X-RAY DIFFRACTION96.1
3.99-4.570.19681510.17771832X-RAY DIFFRACTION96.87
4.57-5.760.21971590.18411803X-RAY DIFFRACTION97.13
5.76-63.690.22981600.21431865X-RAY DIFFRACTION96.66

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