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- PDB-4jt8: Crystal Structure of human SIRT3 with ELT inhibitor 28 [4-(4-{2-[... -

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Basic information

Entry
Database: PDB / ID: 4jt8
TitleCrystal Structure of human SIRT3 with ELT inhibitor 28 [4-(4-{2-[(2,2-dimethylpropanoyl)amino]ethyl}piperidin-1-yl)thieno[3,2-d]pyrimidine-6-carboxamide[
ComponentsNAD-dependent protein deacetylase sirtuin-3, mitochondrial
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Deacetylase / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of catalase activity / positive regulation of ceramide biosynthetic process / positive regulation of superoxide dismutase activity / Maturation of TCA enzymes and regulation of TCA cycle / peptidyl-lysine deacetylation / NAD-dependent protein lysine deacetylase activity / protein acetyllysine N-acetyltransferase / histone deacetylase activity, NAD-dependent / protein deacetylation / Regulation of FOXO transcriptional activity by acetylation ...positive regulation of catalase activity / positive regulation of ceramide biosynthetic process / positive regulation of superoxide dismutase activity / Maturation of TCA enzymes and regulation of TCA cycle / peptidyl-lysine deacetylation / NAD-dependent protein lysine deacetylase activity / protein acetyllysine N-acetyltransferase / histone deacetylase activity, NAD-dependent / protein deacetylation / Regulation of FOXO transcriptional activity by acetylation / NAD+ binding / negative regulation of reactive oxygen species metabolic process / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / aerobic respiration / Transcriptional activation of mitochondrial biogenesis / positive regulation of insulin secretion / negative regulation of ERK1 and ERK2 cascade / transferase activity / sequence-specific DNA binding / mitochondrial matrix / enzyme binding / protein-containing complex / mitochondrion / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
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 ...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-1NR / NAD-dependent protein deacetylase sirtuin-3, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.26 Å
AuthorsDai, H.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Discovery of Thieno[3,2-d]pyrimidine-6-carboxamides as Potent Inhibitors of SIRT1, SIRT2, and SIRT3.
Authors: Disch, J.S. / Evindar, G. / Chiu, C.H. / Blum, C.A. / Dai, H. / Jin, L. / Schuman, E. / Lind, K.E. / Belyanskaya, S.L. / Deng, J. / Coppo, F. / Aquilani, L. / Graybill, T.L. / Cuozzo, J.W. / ...Authors: Disch, J.S. / Evindar, G. / Chiu, C.H. / Blum, C.A. / Dai, H. / Jin, L. / Schuman, E. / Lind, K.E. / Belyanskaya, S.L. / Deng, J. / Coppo, F. / Aquilani, L. / Graybill, T.L. / Cuozzo, J.W. / Lavu, S. / Mao, C. / Vlasuk, G.P. / Perni, R.B.
History
DepositionMar 22, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 24, 2013Provider: repository / Type: Initial release
Revision 1.1Jul 3, 2013Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: NAD-dependent protein deacetylase sirtuin-3, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0673
Polymers31,6121
Non-polymers4552
Water1,27971
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)117.280, 117.280, 45.590
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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Components

#1: Protein NAD-dependent protein deacetylase sirtuin-3, mitochondrial / hSIRT3 / Regulatory protein SIR2 homolog 3 / SIR2-like protein 3


Mass: 31612.348 Da / Num. of mol.: 1 / Fragment: UNP residues 118-399
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT3, SIR2L3 / Production host: Escherichia coli (E. coli)
References: UniProt: Q9NTG7, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-1NR / 4-(4-{2-[(2,2-dimethylpropanoyl)amino]ethyl}piperidin-1-yl)thieno[3,2-d]pyrimidine-6-carboxamide


Mass: 389.515 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H27N5O2S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 71 / 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: 2.86 Å3/Da / Density % sol: 57.04 %
Crystal growMethod: vapor diffusion, hanging drop / Details: VAPOR DIFFUSION, HANGING DROP

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.26→38.39 Å / Num. obs: 16046

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Processing

SoftwareName: REFMAC / Version: 5.5.0109 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.26→38.39 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.938 / SU B: 6.401 / SU ML: 0.156 / Cross valid method: THROUGHOUT / ESU R: 0.262 / ESU R Free: 0.208 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24074 856 5.1 %RANDOM
Rwork0.20167 ---
obs0.20359 16046 99.69 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 42.747 Å2
Baniso -1Baniso -2Baniso -3
1-0.07 Å20.04 Å20 Å2
2--0.07 Å20 Å2
3----0.11 Å2
Refinement stepCycle: LAST / Resolution: 2.26→38.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2145 0 28 71 2244
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222229
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2421.9973039
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3465273
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.69622.81396
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.65515354
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.5381519
X-RAY DIFFRACTIONr_chiral_restr0.0820.2341
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0221710
X-RAY DIFFRACTIONr_gen_planes_other
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_it0.5241.51372
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.01722229
X-RAY DIFFRACTIONr_scbond_it1.4653857
X-RAY DIFFRACTIONr_scangle_it2.5724.5810
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.26→2.322 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.345 58 -
Rwork0.258 1162 -
obs--98.79 %

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