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- PDB-9cbt: Crystal structure of human sirtuin 3 fragment (residues 118-399) ... -

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Basic information

Entry
Database: PDB / ID: 9cbt
TitleCrystal structure of human sirtuin 3 fragment (residues 118-399) bound to intermediates from reaction with NAD and inhibitor NH6-10
ComponentsNAD-dependent protein deacetylase sirtuin-3, mitochondrial
KeywordsHYDROLASE / Deacetylase
Function / homology
Function and homology information


positive regulation of superoxide dismutase activity / positive regulation of catalase activity / NAD-dependent protein lysine delactylase activity / positive regulation of ceramide biosynthetic process / peptidyl-lysine deacetylation / Maturation of TCA enzymes and regulation of TCA cycle / NAD-dependent protein lysine deacetylase activity / protein acetyllysine N-acetyltransferase / histone H3K14 deacetylase activity, NAD-dependent / histone H3K9 deacetylase activity, NAD-dependent ...positive regulation of superoxide dismutase activity / positive regulation of catalase activity / NAD-dependent protein lysine delactylase activity / positive regulation of ceramide biosynthetic process / peptidyl-lysine deacetylation / Maturation of TCA enzymes and regulation of TCA cycle / 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 / histone deacetylase activity, NAD-dependent / protein deacetylation / positive regulation of oxidative phosphorylation / Regulation of FOXO transcriptional activity by acetylation / protein lysine deacetylase activity / cellular response to stress / negative regulation of reactive oxygen species metabolic process / NAD+ binding / Mitochondrial unfolded protein response (UPRmt) / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / aerobic respiration / Transcriptional activation of mitochondrial biogenesis / negative regulation of ERK1 and ERK2 cascade / positive regulation of insulin secretion / sequence-specific DNA binding / mitochondrial matrix / enzyme binding / protein-containing complex / mitochondrion / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
Sirtuin, catalytic core small domain superfamily / Sirtuin family / : / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / DHS-like NAD/FAD-binding domain superfamily
Similarity search - Domain/homology
: / : / NAD-dependent protein deacetylase sirtuin-3, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.95 Å
AuthorsFenwick, M.K. / Young, H.J. / Lin, H.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK107868-04 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM124165-01 United States
National Institutes of Health/Office of the DirectorS10OD021527 United States
Department of Energy (DOE, United States)DE-AC02-06CH11357 United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: A Mitochondria-Targeting SIRT3 Inhibitor with Activity against Diffuse Large B Cell Lymphoma.
Authors: Jana, S. / Shang, J. / Hong, J.Y. / Fenwick, M.K. / Puri, R. / Lu, X. / Melnick, A.M. / Li, M. / Lin, H.
History
DepositionJun 20, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 7, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 19, 2025Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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 / _pdbx_entry_details.has_protein_modification

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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
B: NAD-dependent protein deacetylase sirtuin-3, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,3567
Polymers62,6802
Non-polymers2,6765
Water6,449358
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A: NAD-dependent protein deacetylase sirtuin-3, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5813
Polymers31,3401
Non-polymers1,2412
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: NAD-dependent protein deacetylase sirtuin-3, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7754
Polymers31,3401
Non-polymers1,4353
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)39.433, 63.193, 114.608
Angle α, β, γ (deg.)90.000, 90.790, 90.000
Int Tables number4
Space group name H-MP1211
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein NAD-dependent protein deacetylase sirtuin-3, mitochondrial


Mass: 31340.084 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT3 / Plasmid: pSUMO / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / Variant (production host): Rosetta / References: UniProt: Q9NTG7

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Non-polymers , 5 types, 363 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-5IA / 2-{[(2S)-6-[(Z)-(1-{[(2R,3R,4R,5R)-5-({[(R)-{[(R)-{[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl]oxy}(hydroxy)phosphoryl]oxy}methyl)-4-hydroxy-2-sulfanyloxolan-3-yl]oxy}tetradecylidene)amino]-2-{[(benzyloxy)carbonyl]amino}hexanoyl]amino}-N,N,N-triethylethan-1-aminium (non-preferred name)


Mass: 1175.292 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C51H86N9O16P2S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#5: Chemical ChemComp-5I7 / (phenylmethyl) ~{N}-[(2~{S})-6-[[(2~{R},3~{a}~{R},5~{R},6~{R},6~{a}~{R})-5-[[[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl]oxy-oxidanyl-phosphoryl]oxymethyl]-6-oxidanyl-2-tridecyl-3~{a},5,6,6~{a}-tetrahydrofuro[2,3-d][1,3]oxathiol-2-yl]amino]-1-oxidanylidene-1-[2-(triethyl-$l^{4}-azanyl)ethylamino]hexan-2-yl]carbamate


Mass: 1175.292 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C51H86N9O16P2S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 358 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.28 Å3/Da / Density % sol: 46 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop
Details: 100 mM Tris, pH 7.9, 100 mM MgCl2, 20 % w/v PEG8000, and 17.5 % w/v PEG400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 8, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 1.95→39.43 Å / Num. obs: 40149 / % possible obs: 97.4 % / Redundancy: 3 % / Biso Wilson estimate: 35.08 Å2 / CC1/2: 0.991 / Rmerge(I) obs: 0.1 / Rpim(I) all: 0.067 / Rrim(I) all: 0.121 / Net I/σ(I): 5.3 / Num. measured all: 119067 / Scaling rejects: 66
Reflection shellResolution: 1.95→2 Å / Redundancy: 3 % / Rmerge(I) obs: 0.886 / Num. measured all: 8478 / Num. unique obs: 2834 / CC1/2: 0.663 / Rpim(I) all: 0.588 / Rrim(I) all: 1.068 / Net I/σ(I) obs: 1 / % possible all: 99.1

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3.12 Å39.43 Å
Translation3.12 Å39.43 Å

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
Aimless0.7.4data scaling
PHASER2.8.3phasing
PDB_EXTRACT3.27data extraction
Coot0.8.9.2model building
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→39.43 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 30.91 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2391 2046 5.11 %
Rwork0.1984 38025 -
obs0.2005 40071 97.16 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 119.85 Å2 / Biso mean: 47.5708 Å2 / Biso min: 21.48 Å2
Refinement stepCycle: final / Resolution: 1.95→39.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4250 0 173 358 4781
Biso mean--42.98 49.96 -
Num. residues----544
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.95-20.43771250.38532544266999
2-2.050.3781350.34322561269699
2.05-2.10.40521770.30482520269798
2.1-2.160.29111240.2842539266398
2.16-2.230.28271230.25882541266498
2.23-2.310.33951210.25242588270998
2.31-2.40.30571180.24322558267698
2.4-2.510.30681800.22422470265097
2.51-2.650.30031210.21612529265096
2.65-2.810.23851330.20362534266797
2.81-3.030.26381310.19792530266197
3.03-3.330.21451390.19632534267397
3.33-3.820.20571640.1752476264096
3.82-4.810.18981330.15052551268496
4.81-39.430.18381220.16412550267294
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)
10.6927-0.1436-0.14651.6822-1.4373.60730.0677-0.010.2133-0.2016-0.1578-0.40610.00010.09720.08330.47770.05070.25070.35740.08520.541624.552818.917811.8591
29.1378-4.84822.76955.2562-4.46814.2384-0.1913-0.5051.45540.7858-0.4708-0.7148-1.48030.06060.82650.7067-0.03680.15540.3647-0.0040.686626.076828.736123.9321
30.52560.23160.35940.5326-0.66253.25010.05820.14230.2423-0.01820.09090.0579-0.2463-0.1514-0.13680.42220.02830.16870.37430.08440.477415.972318.522712.4375
42.7321-0.5541-2.03423.424-0.06673.53810.2317-0.10850.1897-0.2424-0.0737-0.4807-0.13340.3404-0.12670.1843-0.024-0.06850.2442-0.03090.294423.3616-5.725245.5816
57.53585.0887-6.97673.5818-4.78736.4785-1.08650.827-0.5151-1.09630.5111-0.4211.6567-0.70960.55340.58170.0112-0.04580.3457-0.05610.522921.8838-16.419334.4482
60.7660.2775-0.42811.4992-0.67113.58290.0410.14590.0484-0.30720.0768-0.04730.1542-0.0675-0.09880.27170.0006-0.01740.2525-0.00020.290714.4276-3.890838.2184
72.5691-0.7162-0.12463.9833-0.38022.89890.0018-0.077-0.11530.14010.0934-0.23860.08990.067-0.09540.24820.0197-0.03390.22540.01390.203114.8577-4.810657.0567
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 122 through 189 )A122 - 189
2X-RAY DIFFRACTION2chain 'A' and (resid 190 through 207 )A190 - 207
3X-RAY DIFFRACTION3chain 'A' and (resid 208 through 255 or resid 257 through 258 or resid 260 through 279 or resid 281 through 282 or resid 284 through 391)A208 - 255
4X-RAY DIFFRACTION3chain 'A' and (resid 208 through 255 or resid 257 through 258 or resid 260 through 279 or resid 281 through 282 or resid 284 through 391)A257 - 258
5X-RAY DIFFRACTION3chain 'A' and (resid 208 through 255 or resid 257 through 258 or resid 260 through 279 or resid 281 through 282 or resid 284 through 391)A260
6X-RAY DIFFRACTION3chain 'A' and (resid 208 through 255 or resid 257 through 258 or resid 260 through 279 or resid 281 through 282 or resid 284 through 391)A281 - 282
7X-RAY DIFFRACTION3chain 'A' and (resid 208 through 255 or resid 257 through 258 or resid 260 through 279 or resid 281 through 282 or resid 284 through 391)A284 - 391
8X-RAY DIFFRACTION4chain 'B' and (resid 122 through 189 )B122 - 189
9X-RAY DIFFRACTION5chain 'B' and (resid 190 through 207 )B190 - 207
10X-RAY DIFFRACTION6chain 'B' and (resid 208 through 255 or resid 257 through 258 or resid 260 through 279 or resid 281 through 282 or resid 284 through 327)B208 - 255
11X-RAY DIFFRACTION6chain 'B' and (resid 208 through 255 or resid 257 through 258 or resid 260 through 279 or resid 281 through 282 or resid 284 through 327)B257 - 258
12X-RAY DIFFRACTION6chain 'B' and (resid 208 through 255 or resid 257 through 258 or resid 260 through 279 or resid 281 through 282 or resid 284 through 327)B281 - 282
13X-RAY DIFFRACTION6chain 'B' and (resid 208 through 255 or resid 257 through 258 or resid 260 through 279 or resid 281 through 282 or resid 284 through 327)B284 - 327
14X-RAY DIFFRACTION7chain 'B' and (resid 328 through 395 )B328 - 395

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