PDB-7t1d: Human SIRT2 in complex with small molecule 359

ID or keywords:

Entry

Database: PDB / ID: 7t1d

Title

Human SIRT2 in complex with small molecule 359

Components

NAD-dependent protein deacetylase sirtuin-2

Keywords

HYDROLASE/INHIBITOR / Allosteric inhibitor / 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 / histone H4K16 deacetylase activity, NAD-dependent / 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 ...cellular response to caloric restriction / negative regulation of oligodendrocyte progenitor proliferation / : / negative regulation of striated muscle tissue development / negative regulation of satellite cell differentiation / histone H4K16 deacetylase activity, NAD-dependent / 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 / tubulin deacetylation / paranodal junction / lateral loop / NLRP3 inflammasome complex assembly / peptidyl-lysine deacetylation / 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 / NAD-dependent protein lysine deacetylase activity / positive regulation of fatty acid biosynthetic process / rDNA heterochromatin formation / myelination in peripheral nervous system / protein acetyllysine N-acetyltransferase / histone deacetylase activity, NAD-dependent / chromatin silencing complex / Initiation of Nuclear Envelope (NE) Reformation / protein deacetylation / positive regulation of oocyte maturation / regulation of phosphorylation / juxtaparanode region of axon / protein lysine deacetylase activity / meiotic spindle / response to redox state / regulation of myelination / histone deacetylase activity / histone acetyltransferase binding / positive regulation of DNA binding / negative regulation of fat cell differentiation / negative regulation of peptidyl-threonine phosphorylation / positive regulation of execution phase of apoptosis / positive regulation of cell division / glial cell projection / NAD+-protein poly-ADP-ribosyltransferase activity / NAD+ binding / subtelomeric heterochromatin formation / negative regulation of reactive oxygen species metabolic process / heterochromatin / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / cellular response to epinephrine stimulus / substantia nigra development / centriole / epigenetic regulation of gene expression / negative regulation of autophagy / ubiquitin binding / meiotic cell cycle / negative regulation of protein catabolic process / heterochromatin formation / mitotic spindle / histone deacetylase binding / autophagy / spindle / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / myelin sheath / chromosome / cellular response to oxidative stress / cellular response to hypoxia / midbody / growth cone / perikaryon / DNA-binding transcription factor binding / proteasome-mediated ubiquitin-dependent protein catabolic process / microtubule / chromosome, telomeric region / regulation of cell cycle / cell division / innate immune response / 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

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT /

molecular replacement / Resolution: 1.75 Å

Authors

Kulp, J.L. / Remiszewski, S. / Todd, M. / Chiang, L.W.

Funding support

United States, 1items

Citation

Journal: J.Clin.Invest. / Year: 2023
Title: An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity.
Authors: Roche, K.L. / Remiszewski, S. / Todd, M.J. / Kulp 3rd, J.L. / Tang, L. / Welsh, A.V. / Barry, A.P. / De, C. / Reiley, W.W. / Wahl, A. / Garcia, J.V. / Luftig, M.A. / Shenk, T. / Tonra, J.R. ...

History

Deposition	Dec 1, 2021	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	May 17, 2023	Provider: repository / Type: Initial release
Revision 1.1	Jun 28, 2023	Group: Database references / Category: citation / citation_author 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2	Oct 25, 2023	Group: Data collection / Database references ...Data collection / Database references / Source and taxonomy / Structure summary Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / entity / entity_name_com / entity_src_gen / pdbx_entity_src_syn / struct_ref / struct_ref_seq Item: _entity.pdbx_ec / _entity.src_method ..._entity.pdbx_ec / _entity.src_method / _struct_ref.db_code / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_db_accession / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_db_accession
Revision 1.3	Apr 3, 2024	Group: Refinement description / Category: pdbx_initial_refinement_model

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	7t1d.cif.gz	162.2 KB	Display	PDBx/mmCIF format
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Validation report

Summary document	7t1d_validation.pdf.gz	948.1 KB	Display	wwPDB validaton report
Full document	7t1d_full_validation.pdf.gz	957.9 KB	Display
Data in XML	7t1d_validation.xml.gz	32.6 KB	Display
Data in CIF	7t1d_validation.cif.gz	49.1 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/t1/7t1d ftp://data.pdbj.org/pub/pdb/validation_reports/t1/7t1d	HTTPS FTP

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Related structure data

Similar structure data	Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

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Links

PDB pages	PDBj / wwPDB / NCBI
Related items in Molecule of the Month	#213 - Sep 2017 Sirtuins similarity (10) #263 - Nov 2021 Acetohydroxyacid Synthase similarity (1) #85 - Jan 2007 Importins similarity (1)

Deposited unit

A: NAD-dependent protein deacetylase sirtuin-2

B: NAD-dependent protein deacetylase sirtuin-2

hetero molecules

70.2 kDa, 2 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

Idetical with deposited unit
defined by author&software

Unit cell

Length a, b, c (Å)	36.775, 55.980, 139.576
Angle α, β, γ (deg.)	90.000, 94.462, 90.000
Int Tables number	4
Space group name H-M	P12₁1

Noncrystallographic symmetry (NCS)

NCS domain:

ID	Ens-ID	Details
1	1	A
2	1	B

NCS domain segments:

Ens-ID: 1 / Beg auth comp-ID: GLU / Beg label comp-ID: GLU / End auth comp-ID: GLN / End label comp-ID: GLN / Refine code: 1 / Auth seq-ID: 56 - 355 / Label seq-ID: 1 - 300

Dom-ID	Component-ID	Auth asym-ID	Label asym-ID
1	1	A	A
2	2	B	B

NCS ensembles : (Details: Local NCS retraints between domains: 1 2)

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Protein , 1 types, 2 molecules AB

#1: Protein	NAD-dependent protein deacetylase sirtuin-2 Mass: 34090.336 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q8IXJ6

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Non-polymers , 6 types, 698 molecules

#2: Chemical	ChemComp-ZN / ZINC ION Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical	ChemComp-SO4 / SULFATE ION Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO₄
#4: Chemical	ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C₂H₆O₂
#5: Chemical	ChemComp-DMS / DIMETHYL SULFOXIDE Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂H₆OS / Comment: DMSO, precipitant*YM
#6: Chemical	ChemComp-E7K / 7-(2,4-dimethyl-1H-imidazol-1-yl)-2-(5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-1,3-thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline Mass: 466.601 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂₇H₂₆N₆S / Feature type: SUBJECT OF INVESTIGATION
#7: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 681 / Source method: isolated from a natural source / Formula: H₂O

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Details

Has ligand of interest	Y

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 2.08 Å³/Da / Density % sol: 40.89 %
Crystal grow	Temperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 8 Details: Crystals of SIRT2 in complex with FLS-359 were obtained using hanging-drop vapour diffusion setups. SIRT2 at a concentration of 21.9 mg/ml (50 mM Hepes-NaOH, 150 mM NaCl, pH 8.0) was ...Details: Crystals of SIRT2 in complex with FLS-359 were obtained using hanging-drop vapour diffusion setups. SIRT2 at a concentration of 21.9 mg/ml (50 mM Hepes-NaOH, 150 mM NaCl, pH 8.0) was preincubated with 3.6 mM (5.7-fold molar excess) of FLS-359 (100 mM in DMSO) for 1 h. 1 ul of the protein solution was then mixed with 2 ul of reservoir solution (0.1 M Hepes-NaOH pH 6.6, 0.3 M Li2SO4, 21 % (w/v) PEG 3350) and streak seeded before being equilibrated at 20C over 0.2 ml of reservoir solution. Well diffracting crystals grew as thick aggregates of thin plates and were mounted within 19 days

Crystal

Density Matthews: 2.08 Å³/Da / Density % sol: 40.89 %

Crystal grow

Temperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 8
Details: Crystals of SIRT2 in complex with FLS-359 were obtained using hanging-drop vapour diffusion setups. SIRT2 at a concentration of 21.9 mg/ml (50 mM Hepes-NaOH, 150 mM NaCl, pH 8.0) was ...

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Data collection

Diffraction

Mean temperature: 100 K / Serial crystal experiment: N

Diffraction source

Source:

SYNCHROTRON / Site:

ESRF

/ Beamline: MASSIF-1 / Wavelength: 1.0332 Å

Detector

Type: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Sep 1, 2020

Radiation

Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray

Radiation wavelength

Wavelength: 1.0332 Å / Relative weight: 1

Reflection

Resolution: 1.75→139.15 Å / Num. obs: 56312 / % possible obs: 98.6 % / Redundancy: 3.5 % / CC_1/2: 0.996 / R_merge(I) obs: 0.075 / R_pim(I) all: 0.047 / R_rim(I) all: 0.089 / Net I/σ(I): 9.5 / Num. measured all: 194963 / Scaling rejects: 128

Reflection shell

Diffraction-ID: 1 / Redundancy: 3.4 %

Resolution (Å)	R_merge(I) obs	Num. measured all	Num. unique obs	CC_1/2	R_pim(I) all	R_rim(I) all	Net I/σ(I) obs	% possible all
1.75-1.78	0.612	10269	3005	0.664	0.388	0.727	1.9	98.9
9.09-139.15	0.04	1502	443	0.992	0.025	0.048	26.7	99.6

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Phasing

Phasing	Method: molecular replacement

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0267	refinement
Aimless	0.7.4	data scaling
PDB_EXTRACT	3.27	data extraction
XDS		data reduction
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: CRELUX reference structure of SIRT2

Resolution: 1.75→35.002 Å / Cor.coef. F_o:F_c: 0.967 / Cor.coef. F_o:F_c free: 0.944 / WR_factor R_free: 0.205 / WR_factor R_work: 0.155 / SU B: 2.882 / SU ML: 0.091 / Average fsc free: 0.9223 / Average fsc work: 0.936 / Cross valid method: THROUGHOUT / ESU R: 0.126 / ESU R Free: 0.125
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection	Selection details
R_free	0.2128	2843	5.051 %	RANDOM
R_work	0.163	53442	-	-
all	0.166	-	-	-
obs	-	56285	98.316 %	-

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT

Displacement parameters

B_iso mean: 25.623 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	0.054 Å²	-0 Å²	0.172 Å²
2-	-	-0.358 Å²	0 Å²
3-	-	-	0.274 Å²

Refinement step

Cycle: LAST / Resolution: 1.75→35.002 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	4701	0	126	681	5508

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.01	0.013	5156
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.015	4855
X-RAY DIFFRACTION	r_angle_refined_deg	1.574	1.667	6975
X-RAY DIFFRACTION	r_angle_other_deg	1.364	1.592	11249
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	6.89	5	631
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	32.859	21.875	256
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	14.127	15	908
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	19.024	15	33
X-RAY DIFFRACTION	r_chiral_restr	0.082	0.2	623
X-RAY DIFFRACTION	r_gen_planes_refined	0.008	0.02	5768
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	1170
X-RAY DIFFRACTION	r_nbd_refined	0.215	0.2	1131
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.184	0.2	4654
X-RAY DIFFRACTION	r_nbtor_refined	0.168	0.2	2468
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.077	0.2	2173
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.191	0.2	547
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.06	0.2	4
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.147	0.2	36
X-RAY DIFFRACTION	r_nbd_other	0.182	0.2	94
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.203	0.2	41
X-RAY DIFFRACTION	r_mcbond_it	2.221	2.428	2473
X-RAY DIFFRACTION	r_mcbond_other	2.221	2.428	2474
X-RAY DIFFRACTION	r_mcangle_it	3.279	3.615	3121
X-RAY DIFFRACTION	r_mcangle_other	3.28	3.617	3122
X-RAY DIFFRACTION	r_scbond_it	2.801	2.782	2683
X-RAY DIFFRACTION	r_scbond_other	2.8	2.782	2684
X-RAY DIFFRACTION	r_scangle_it	4.178	4.036	3854
X-RAY DIFFRACTION	r_scangle_other	4.178	4.036	3855
X-RAY DIFFRACTION	r_lrange_it	7.101	30.499	6141
X-RAY DIFFRACTION	r_lrange_other	6.948	29.831	5961
X-RAY DIFFRACTION	r_ncsr_local_group_1	0.107	0.05	9344

Refine LS restraints NCS

Ens-ID	Dom-ID	Auth asym-ID	Refine-ID	Type	Rms dev position (Å)	Weight position
1	1	A	X-RAY DIFFRACTION	Local ncs	0.10748	0.05008
1	2	B	X-RAY DIFFRACTION	Local ncs	0.10748	0.05008

LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	R_factor all	Num. reflection all	Fsc free	Fsc work	% reflection obs (%)	WR_factor R_work
1.75-1.795	0.297	187	0.241	3876	0.244	4119	0.826	0.859	98.6404	0.228
1.795-1.844	0.257	177	0.226	3787	0.227	4141	0.886	0.897	95.7257	0.207
1.844-1.898	0.23	180	0.21	3715	0.211	3940	0.906	0.91	98.8579	0.189
1.898-1.956	0.262	185	0.196	3572	0.199	3891	0.888	0.917	96.5562	0.176
1.956-2.02	0.226	179	0.183	3502	0.185	3738	0.921	0.933	98.4751	0.164
2.02-2.091	0.236	194	0.175	3379	0.178	3659	0.919	0.938	97.6496	0.157
2.091-2.169	0.195	189	0.171	3239	0.172	3528	0.944	0.948	97.1655	0.153
2.169-2.257	0.227	178	0.166	3143	0.169	3335	0.928	0.947	99.5802	0.15
2.257-2.357	0.203	147	0.156	3026	0.158	3242	0.946	0.954	97.8717	0.142
2.357-2.472	0.218	171	0.152	2902	0.155	3131	0.932	0.953	98.1476	0.139
2.472-2.605	0.233	153	0.157	2768	0.161	2935	0.932	0.95	99.523	0.146
2.605-2.762	0.22	143	0.156	2634	0.159	2809	0.933	0.95	98.8608	0.147
2.762-2.951	0.219	132	0.154	2466	0.157	2628	0.94	0.952	98.8584	0.146
2.951-3.186	0.217	107	0.154	2351	0.157	2479	0.94	0.959	99.1529	0.149
3.186-3.487	0.178	136	0.155	2095	0.157	2249	0.955	0.962	99.1996	0.154
3.487-3.894	0.216	123	0.146	1929	0.15	2062	0.948	0.963	99.515	0.149
3.894-4.487	0.153	94	0.134	1737	0.135	1837	0.969	0.969	99.6734	0.141
4.487-5.473	0.239	77	0.143	1458	0.147	1546	0.949	0.975	99.2885	0.15
5.473-7.647	0.191	51	0.171	1173	0.171	1228	0.963	0.962	99.6743	0.176
7.647-35.002	0.208	40	0.177	690	0.179	732	0.952	0.959	99.7268	0.186

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