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- PDB-4i5i: Crystal structure of the SIRT1 catalytic domain bound to NAD and ... -

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Basic information

Entry
Database: PDB / ID: 4i5i
TitleCrystal structure of the SIRT1 catalytic domain bound to NAD and an EX527 analog
ComponentsNAD-dependent protein deacetylase sirtuin-1
KeywordsHYDROLASE / Rossmann Fold / histone deacetylase / epigenetics / cancer / sirtuin / acetylated lysine of histone
Function / homology
Function and homology information


negative regulation of prostaglandin biosynthetic process / regulation of smooth muscle cell apoptotic process / maintenance of nucleus location / histone H3K deacetylase activity / histone decrotonylase activity, NAD-dependent / negative regulation of protein acetylation / negative regulation of attachment of mitotic spindle microtubules to kinetochore / negative regulation of cellular response to testosterone stimulus / regulation of endodeoxyribonuclease activity / positive regulation of cAMP-dependent protein kinase activity ...negative regulation of prostaglandin biosynthetic process / regulation of smooth muscle cell apoptotic process / maintenance of nucleus location / histone H3K deacetylase activity / histone decrotonylase activity, NAD-dependent / negative regulation of protein acetylation / negative regulation of attachment of mitotic spindle microtubules to kinetochore / negative regulation of cellular response to testosterone stimulus / regulation of endodeoxyribonuclease activity / positive regulation of cAMP-dependent protein kinase activity / negative regulation of peptidyl-lysine acetylation / histone H3K14 deacetylase activity, NAD-dependent / eNoSc complex / regulation of peroxisome proliferator activated receptor signaling pathway / peptidyl-lysine acetylation / protein depropionylation / NAD-dependent protein-lysine depropionylase activity / positive regulation of macrophage apoptotic process / histone H4K12 deacetylase activity, hydrolytic mechanism / negative regulation of triglyceride biosynthetic process / behavioral response to starvation / pyrimidine dimer repair by nucleotide-excision repair / triglyceride mobilization / keratin filament binding / NAD-dependent protein lysine delactylase activity / leptin-mediated signaling pathway / histone H3K9 deacetylase activity, NAD-dependent / negative regulation of phosphorylation / Regulation of MITF-M dependent genes involved in metabolism / regulation of lipid storage / regulation of brown fat cell differentiation / positive regulation of smooth muscle cell differentiation / bHLH transcription factor binding / histone H4K16 deacetylase activity, NAD-dependent / intracellular triglyceride homeostasis / positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / HLH domain binding / response to leptin / regulation of transcription by glucose / deacetylase activity / regulation of bile acid biosynthetic process / ovulation from ovarian follicle / positive regulation of adaptive immune response / regulation of centrosome duplication / negative regulation of androgen receptor signaling pathway / single strand break repair / rDNA heterochromatin / protein acetyllysine N-acetyltransferase / protein deacetylation / NAD-dependent protein lysine deacetylase activity / histone deacetylase activity, NAD-dependent / rDNA heterochromatin formation / positive regulation of MHC class II biosynthetic process / chromatin silencing complex / negative regulation of TOR signaling / Regulation of FOXO transcriptional activity by acetylation / mitogen-activated protein kinase binding / histone deacetylase activity / protein lysine deacetylase activity / nuclear inner membrane / stress-induced premature senescence / : / positive regulation of macrophage cytokine production / UV-damage excision repair / muscle organ development / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / DNA methylation-dependent constitutive heterochromatin formation / negative regulation of fat cell differentiation / positive regulation of double-strand break repair / DNA synthesis involved in DNA repair / negative regulation of DNA damage response, signal transduction by p53 class mediator / DNA repair-dependent chromatin remodeling / negative regulation of signal transduction by p53 class mediator / negative regulation of cell cycle / regulation of glucose metabolic process / negative regulation of cellular senescence / macrophage differentiation / white fat cell differentiation / positive regulation of macroautophagy / NAD+ binding / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of cholesterol efflux / Regulation of HSF1-mediated heat shock response / positive regulation of blood vessel endothelial cell migration / fatty acid homeostasis / positive regulation of insulin receptor signaling pathway / negative regulation of hippo signaling / subtelomeric heterochromatin formation / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / transcription regulator inhibitor activity / regulation of cellular response to heat / cellular response to glucose starvation / energy homeostasis / endoplasmic reticulum unfolded protein response / heterochromatin / positive regulation of endothelial cell proliferation / positive regulation of adipose tissue development / Transcriptional and post-translational regulation of MITF-M expression and activity / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / transforming growth factor beta receptor signaling pathway
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-4I5 / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NAD-dependent protein deacetylase sirtuin-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsZhao, X. / Allison, D. / Condon, B. / Zhang, F. / Gheyi, T. / Zhang, A. / Ashok, S. / Russell, M. / Macewan, I. / Qian, Y. ...Zhao, X. / Allison, D. / Condon, B. / Zhang, F. / Gheyi, T. / Zhang, A. / Ashok, S. / Russell, M. / Macewan, I. / Qian, Y. / Jamison, J.A. / Luz, J.G.
CitationJournal: J.Med.Chem. / Year: 2013
Title: The 2.5 angstrom crystal structure of the SIRT1 catalytic domain bound to nicotinamide adenine dinucleotide (NAD+) and an indole (EX527 analogue) reveals a novel mechanism of histone deacetylase inhibition.
Authors: Zhao, X. / Allison, D. / Condon, B. / Zhang, F. / Gheyi, T. / Zhang, A. / Ashok, S. / Russell, M. / MacEwan, I. / Qian, Y. / Jamison, J.A. / Luz, J.G.
History
DepositionNov 28, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 23, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 28, 2013Group: Database references
Revision 1.2Nov 12, 2014Group: Structure summary
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_label_asym_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

Downloads & links

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Assembly

Deposited unit
A: NAD-dependent protein deacetylase sirtuin-1
B: NAD-dependent protein deacetylase sirtuin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,0258
Polymers65,0412
Non-polymers1,9836
Water2,918162
1
A: NAD-dependent protein deacetylase sirtuin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,5124
Polymers32,5211
Non-polymers9923
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: NAD-dependent protein deacetylase sirtuin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,5124
Polymers32,5211
Non-polymers9923
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4400 Å2
ΔGint-15 kcal/mol
Surface area24780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)106.513, 106.513, 80.663
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number145
Space group name H-MP32

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Components

#1: Protein NAD-dependent protein deacetylase sirtuin-1 / hSIRT1 / Regulatory protein SIR2 homolog 1 / SIR2-like protein 1 / hSIR2 / SirtT1 75 kDa fragment / 75SirT1


Mass: 32520.723 Da / Num. of mol.: 2
Fragment: Deacetylase sirtuin-type catalytic domain residues 241-516
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT1, SIR2L1 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q96EB6, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides
#2: Chemical ChemComp-4I5 / (6S)-2-chloro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-6-carboxamide


Mass: 262.735 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H15ClN2O
#3: Chemical ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 162 / 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: 4.06 Å3/Da / Density % sol: 69.72 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 5.4
Details: 300 mM NDSB-195 + 100 mM MES pH 5.4 + 1500 mM Sodium Potassium Tartrate, VAPOR DIFFUSION, HANGING DROP, temperature 294K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97929 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Oct 11, 2009
RadiationMonochromator: Kohzu HLD-4 Double Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97929 Å / Relative weight: 1
ReflectionResolution: 2.5→32.2 Å / Num. all: 35389 / Num. obs: 35389 / % possible obs: 100 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1
Reflection shellResolution: 2.5→2.64 Å / % possible all: 100

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Processing

Software
NameVersionClassification
PHASERphasing
REFMAC5.7.0017refinement
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2H2H

2h2h


Resolution: 2.5→30 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.925 / SU B: 5.201 / SU ML: 0.117 / Cross valid method: THROUGHOUT / ESU R: 0.23 / ESU R Free: 0.182 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.19532 1772 5 %RANDOM
Rwork0.16737 ---
obs0.16878 33617 99.88 %-
all-35389 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 35.601 Å2
Baniso -1Baniso -2Baniso -3
1--0.46 Å2-0.23 Å20 Å2
2---0.46 Å20 Å2
3---0.69 Å2
Refinement stepCycle: LAST / Resolution: 2.5→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4238 0 126 162 4526
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0194471
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1952.0176089
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.7465542
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.9923.989188
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.20815736
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.8431528
X-RAY DIFFRACTIONr_chiral_restr0.080.2686
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0213364
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.5→2.565 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.283 130 -
Rwork0.223 2503 -
obs--99.89 %

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