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- PDB-4zzi: SIRT1/Activator/Inhibitor Complex -

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Basic information

Entry
Database: PDB / ID: 4zzi
TitleSIRT1/Activator/Inhibitor Complex
ComponentsNAD-dependent protein deacetylase sirtuin-1
KeywordsHydrolase/hydrolase inhibitor / Sirtuin / Activator / Deacylase / Complex / Hydrolase-hydrolase inhibitor complex
Function / homology
Function and homology information


negative regulation of prostaglandin biosynthetic process / regulation of smooth muscle cell apoptotic process / maintenance of nucleus location / eNoSc complex / histone H4K12 deacetylase activity / histone H3K deacetylase activity / NAD-dependent histone decrotonylase activity / negative regulation of attachment of mitotic spindle microtubules to kinetochore / negative regulation of cellular response to testosterone stimulus / protein depropionylation ...negative regulation of prostaglandin biosynthetic process / regulation of smooth muscle cell apoptotic process / maintenance of nucleus location / eNoSc complex / histone H4K12 deacetylase activity / histone H3K deacetylase activity / NAD-dependent histone decrotonylase activity / negative regulation of attachment of mitotic spindle microtubules to kinetochore / negative regulation of cellular response to testosterone stimulus / protein depropionylation / protein-propionyllysine depropionylase activity / regulation of peroxisome proliferator activated receptor signaling pathway / regulation of transcription by glucose / regulation of protein serine/threonine kinase activity / positive regulation of macrophage apoptotic process / NAD-dependent histone H3K14 deacetylase activity / negative regulation of triglyceride biosynthetic process / regulation of endodeoxyribonuclease activity / triglyceride mobilization / behavioral response to starvation / pyrimidine dimer repair by nucleotide-excision repair / HLH domain binding / regulation of lipid storage / keratin filament binding / leptin-mediated signaling pathway / NAD-dependent histone H3K9 deacetylase activity / negative regulation of peptidyl-lysine acetylation / NAD-dependent histone H4K16 deacetylase activity / regulation of brown fat cell differentiation / deacetylase activity / positive regulation of smooth muscle cell differentiation / bHLH transcription factor binding / response to leptin / positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / intracellular triglyceride homeostasis / peptidyl-lysine acetylation / negative regulation of androgen receptor signaling pathway / positive regulation of adaptive immune response / regulation of centrosome duplication / rDNA heterochromatin / ovulation from ovarian follicle / single strand break repair / negative regulation of cAMP-dependent protein kinase activity / regulation of bile acid biosynthetic process / NAD-dependent protein lysine deacetylase activity / rDNA heterochromatin formation / protein acetyllysine N-acetyltransferase / negative regulation of protein acetylation / chromatin silencing complex / negative regulation of phosphorylation / DNA methylation-dependent heterochromatin formation / protein deacetylation / NAD-dependent histone deacetylase activity / positive regulation of MHC class II biosynthetic process / UV-damage excision repair / protein lysine deacetylase activity / positive regulation of cAMP-dependent protein kinase activity / negative regulation of TOR signaling / negative regulation of helicase activity / positive regulation of macrophage cytokine production / mitogen-activated protein kinase binding / positive regulation of double-strand break repair / Regulation of FOXO transcriptional activity by acetylation / DNA repair-dependent chromatin remodeling / nuclear inner membrane / muscle organ development / stress-induced premature senescence / histone deacetylase activity / DNA synthesis involved in DNA repair / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / negative regulation of NF-kappaB transcription factor activity / negative regulation of fat cell differentiation / intracellular glucose homeostasis / negative regulation of cellular senescence / negative regulation of DNA damage response, signal transduction by p53 class mediator / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / macrophage differentiation / positive regulation of macroautophagy / negative regulation of cell cycle / white fat cell differentiation / regulation of glucose metabolic process / NAD+ binding / Regulation of HSF1-mediated heat shock response / positive regulation of cholesterol efflux / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of blood vessel endothelial cell migration / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / fatty acid homeostasis / heterochromatin / cellular response to glucose starvation / heterochromatin formation / energy homeostasis / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / regulation of cellular response to heat / positive regulation of insulin receptor signaling pathway / negative regulation of canonical NF-kappaB signal transduction / positive regulation of gluconeogenesis / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / positive regulation of endothelial cell proliferation / regulation of mitotic cell cycle
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 / Rossmann fold ...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-1NS / Chem-4TQ / NAD-dependent protein deacetylase sirtuin-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7346 Å
AuthorsDai, H.
CitationJournal: Nat Commun / Year: 2015
Title: Crystallographic structure of a small molecule SIRT1 activator-enzyme complex.
Authors: Dai, H. / Case, A.W. / Riera, T.V. / Considine, T. / Lee, J.E. / Hamuro, Y. / Zhao, H. / Jiang, Y. / Sweitzer, S.M. / Pietrak, B. / Schwartz, B. / Blum, C.A. / Disch, J.S. / Caldwell, R. / ...Authors: Dai, H. / Case, A.W. / Riera, T.V. / Considine, T. / Lee, J.E. / Hamuro, Y. / Zhao, H. / Jiang, Y. / Sweitzer, S.M. / Pietrak, B. / Schwartz, B. / Blum, C.A. / Disch, J.S. / Caldwell, R. / Szczepankiewicz, B. / Oalmann, C. / Yee Ng, P. / White, B.H. / Casaubon, R. / Narayan, R. / Koppetsch, K. / Bourbonais, F. / Wu, B. / Wang, J. / Qian, D. / Jiang, F. / Mao, C. / Wang, M. / Hu, E. / Wu, J.C. / Perni, R.B. / Vlasuk, G.P. / Ellis, J.L.
History
DepositionMay 22, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 15, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 23, 2015Group: Data collection
Revision 1.2Sep 27, 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_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,0684
Polymers40,1251
Non-polymers9423
Water46826
1
A: NAD-dependent protein deacetylase sirtuin-1
hetero molecules

A: NAD-dependent protein deacetylase sirtuin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,1358
Polymers80,2512
Non-polymers1,8856
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation10_664-y+1,-x+1,-z-1/61
Buried area2020 Å2
ΔGint-20 kcal/mol
Surface area31730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)122.150, 122.150, 104.920
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-825-

HOH

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Components

#1: Protein NAD-dependent protein deacetylase sirtuin-1 / hSIRT1 / Regulatory protein SIR2 homolog 1 / SIR2-like protein 1 / hSIR2


Mass: 40125.262 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT1, SIR2L1 / Production host: Escherichia coli (E. coli)
References: UniProt: Q96EB6, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides
#2: Chemical ChemComp-4TQ / (3S)-1,3-dimethyl-N-[3-(1,3-oxazol-5-yl)phenyl]-6-[3-(trifluoromethyl)phenyl]-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide


Mass: 493.480 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H22F3N5O2
#3: Chemical ChemComp-1NS / 4-(4-{2-[(methylsulfonyl)amino]ethyl}piperidin-1-yl)thieno[3,2-d]pyrimidine-6-carboxamide


Mass: 383.489 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H21N5O3S2
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 26 / 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: 2.82 Å3/Da / Density % sol: 56.32 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 0.55 M Sodium chloride, 0.1 M MES pH 6.5, and 20 % w/v PEG 4000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.12713 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Feb 4, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.12713 Å / Relative weight: 1
ReflectionResolution: 2.73→39.983 Å / Num. obs: 12735 / % possible obs: 99.9 % / Redundancy: 17.6 % / Rmerge(I) obs: 0.053 / Net I/σ(I): 38.8
Reflection shellResolution: 2.73→2.95 Å / Redundancy: 18.2 % / Rmerge(I) obs: 0.803 / Mean I/σ(I) obs: 4 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
PHASERphasing
xia2data reduction
xia2data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3GLU and 4IG9

3glu

4ig9


Resolution: 2.7346→39.983 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 25.81 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2346 636 5.01 %
Rwork0.1908 --
obs0.1931 12698 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.7346→39.983 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2679 0 62 26 2767
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042814
X-RAY DIFFRACTIONf_angle_d0.8983826
X-RAY DIFFRACTIONf_dihedral_angle_d14.8951089
X-RAY DIFFRACTIONf_chiral_restr0.031417
X-RAY DIFFRACTIONf_plane_restr0.007495
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7346-2.94570.30031230.23652344X-RAY DIFFRACTION100
2.9457-3.2420.2841250.2162367X-RAY DIFFRACTION100
3.242-3.71090.26531260.19852377X-RAY DIFFRACTION100
3.7109-4.67420.20961260.17142417X-RAY DIFFRACTION100
4.6742-39.98720.22241360.19052557X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
18.87473.11911.86533.10283.048210.5411-0.155-0.7198-0.41320.71880.2378-1.0511-0.18660.4848-0.40150.87870.2202-0.17170.6228-0.04570.603911.072849.1881-19.4313
23.0485-0.40170.83522.5080.0043.2478-0.06680.15580.25360.34290.13260.4307-0.0805-0.34780.0150.5437-0.0113-0.00990.4987-0.10830.70141.357158.2399-5.5357
39.0527-2.9168-2.50786.69493.81228.4122-0.13170.6869-0.46520.19270.2032-0.84340.79940.4894-0.03920.56650.02590.13890.4412-0.02060.674612.709636.9425-3.7339
46.8198-0.5825-0.34614.08181.65735.5813-0.3298-0.1245-1.51530.7421-0.124-0.0351.1127-0.10420.37480.8648-0.03850.18840.50770.08420.69946.156833.50174.5676
53.43371.8961.23238.06463.81533.188-0.138-0.1013-2.15911.6180.17990.6742.2749-0.4015-0.011.5269-0.2740.50780.7868-0.08661.57364.824520.70442.2094
62.285-0.0691-1.64487.1453-3.16382.74630.43310.7529-2.05940.9348-0.0386-0.82532.5293-0.1825-0.27582.1089-0.25880.14880.7535-0.31131.98727.193912.1608-3.6699
75.45210.4219-1.75095.81291.91532.9907-0.1620.8865-0.68320.4137-0.26790.65870.3768-1.30010.34610.5735-0.0520.18830.9383-0.06040.6054-4.326839.8283-2.2725
88.19152.24241.96586.11231.35586.8906-0.1277-0.0190.41120.3861-0.00740.1113-0.0711-0.05110.13680.46180.06010.07390.4506-0.07830.34663.668153.65073.1571
93.45741.3706-1.47455.5221-5.27268.5197-0.4743-0.7685-0.04461.7298-0.0702-0.2713-0.136-0.26270.59951.0681-0.0274-0.00740.5791-0.1330.516410.500557.618511.1329
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 183 through 216 )
2X-RAY DIFFRACTION2chain 'A' and (resid 217 through 252 )
3X-RAY DIFFRACTION3chain 'A' and (resid 253 through 298 )
4X-RAY DIFFRACTION4chain 'A' and (resid 299 through 361 )
5X-RAY DIFFRACTION5chain 'A' and (resid 362 through 388 )
6X-RAY DIFFRACTION6chain 'A' and (resid 389 through 409 )
7X-RAY DIFFRACTION7chain 'A' and (resid 410 through 447 )
8X-RAY DIFFRACTION8chain 'A' and (resid 448 through 493 )
9X-RAY DIFFRACTION9chain 'A' and (resid 494 through 655 )

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