PDB-6u2s: Structure-based discovery of a novel small-molecule inhibitor of ...

ID or keywords:

Entry

Database: PDB / ID: 6u2s

Title

Structure-based discovery of a novel small-molecule inhibitor of methicillin-resistant S. aureus

Components

Bi-component leukocidin LukED subunit D

Keywords

TOXIN / alpha-toxin / PVL / Leukocidins / MRSA

Function / homology

Function and homology information

cytolysis in another organism / toxin activity / extracellular region
Similarity search - Function

Biological species

Staphylococcus aureus (bacteria)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.5 Å

Authors

Liu, J. / Kozhaya, L. / Torres, V.J. / Unutmaz, D. / Lu, M.

Funding support

United States, 1items

Citation

Journal: J.Biol.Chem. / Year: 2020
Title: Structure-based discovery of a small-molecule inhibitor of methicillin-resistantStaphylococcus aureusvirulence.
Authors: Liu, J. / Kozhaya, L. / Torres, V.J. / Unutmaz, D. / Lu, M.

History

Deposition	Aug 20, 2019	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Mar 25, 2020	Provider: repository / Type: Initial release
Revision 1.1	Apr 1, 2020	Group: Database references / Category: citation / citation_author Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2	May 13, 2020	Group: Database references / Category: citation Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3	Oct 11, 2023	Group: Data collection / Database references / Refinement description Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	6u2s.cif.gz	147.4 KB	Display	PDBx/mmCIF format
PDB format	pdb6u2s.ent.gz	114.3 KB	Display	PDB format
PDBx/mmJSON format	6u2s.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/u2/6u2s ftp://data.pdbj.org/pub/pdb/validation_reports/u2/6u2s	HTTPS FTP

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Related structure data

Related structure data	6u33C 6u3fC 6u3tC 6u3yC 6u49C 6u4pC 1lkfS S: Starting model for refinement C: citing same article (ref.)
Similar structure data	1pvl-d 4p8s-d 4iyc-1 4q1q-2 4eiz-2 6u3f-d 5cfa-1 4iyc-2 4iyc-3 4yhd-5 Search similar-shape structures by Omokage search (details) 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	#261 - Sep 2021 DNA-Sequencing Nanopores similarity (4)

Deposited unit

A: Bi-component leukocidin LukED subunit D

hetero molecules

35 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

Idetical with deposited unit
defined by author&software
Evidence: gel filtration

Unit cell

Length a, b, c (Å)	149.202, 37.769, 77.914
Angle α, β, γ (deg.)	90.000, 119.800, 90.000
Int Tables number	5
Space group name H-M	C121

Components on special symmetry positions

ID	Model	Components
1	1	A-792- HOH

#1: Protein	Bi-component leukocidin LukED subunit D / Gamma-hemolysin component B / Leucotoxin LukD / Leukotoxin LukD / LukNF Mass: 34200.523 Da / Num. of mol.: 1 / Fragment: UNP residues 27-327 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Staphylococcus aureus (bacteria) Gene: lukNF, lukD, BTN44_02870, EP54_14125, EQ90_10595, ER624_13605, HMPREF3211_01500, NCTC10654_01892, NCTC13131_06007, RK64_09800 Production host: Escherichia coli K-12 (bacteria) / References: UniProt: Q93UU8, UniProt: Q2FXB1*PLUS
#2: Chemical	ChemComp-PQJ / fos-choline-14 / tetradecyl 2-(trimethyl-$l^{4}-azanyl)ethyl hydrogen phosphate Mass: 380.523 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₁₉H₄₃NO₄P / Feature type: SUBJECT OF INVESTIGATION
#3: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 433 / Source method: isolated from a natural source / Formula: H₂O
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: 2.82 Å³/Da / Density % sol: 56.39 %
Crystal grow	Temperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5 Details: 10 mg/mL protein in 10 mM fos-choline 14, 30 mM beta-OG, 10 mM sodium acetate, pH 5.4 against reservoir solution of 28% PEG400, 0.2 M magnesium chloride, 0.1 M HEPES, pH 7.5

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: CHESS / Beamline: F1 / Wavelength: 0.977 Å
Detector	Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 16, 2016
Radiation	Monochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.977 Å / Relative weight: 1
Reflection	Resolution: 1.5→67.61 Å / Num. obs: 59415 / % possible obs: 97.8 % / Redundancy: 3.2 % / CC_1/2: 0.989 / R_merge(I) obs: 0.054 / Net I/σ(I): 9.7
Reflection shell	Resolution: 1.5→1.53 Å / Redundancy: 3 % / R_merge(I) obs: 0.27 / Mean I/σ(I) obs: 4.4 / Num. unique obs: 3824 / CC_1/2: 0.961 / % possible all: 84.7

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0155	refinement
PDB_EXTRACT	3.25	data extraction
HKL-2000		data reduction
HKL-2000		data scaling
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: PDB entry 1LKF

1lkf

Resolution: 1.5→67.61 Å / Cor.coef. F_o:F_c: 0.971 / Cor.coef. F_o:F_c free: 0.962 / SU B: 2.622 / SU ML: 0.049 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.063 / ESU R Free: 0.065 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS

	R_factor	Num. reflection	% reflection	Selection details
R_free	0.1883	3038	5.1 %	RANDOM
R_work	0.1623	-	-	-
obs	0.1636	56377	97.72 %	-

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK

Displacement parameters

B_iso max: 80.45 Å² / B_iso mean: 29.138 Å² / B_iso min: 14.65 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-0.08 Å²	0 Å²	-0.37 Å²
2-	-	3.56 Å²	0 Å²
3-	-	-	-1.85 Å²

Refinement step

Cycle: final / Resolution: 1.5→67.61 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	2386	0	31	433	2850
B_iso mean	-	-	26.09	39.33	-
Num. residues	-	-	-	-	296

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.019	0.02	2471
X-RAY DIFFRACTION	r_bond_other_d	0.002	0.02	2262
X-RAY DIFFRACTION	r_angle_refined_deg	1.884	1.932	3344
X-RAY DIFFRACTION	r_angle_other_deg	0.992	3	5208
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	6.806	5	294
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	41.914	25.469	128
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	11.324	15	416
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	14.277	15	8
X-RAY DIFFRACTION	r_chiral_restr	0.126	0.2	347
X-RAY DIFFRACTION	r_gen_planes_refined	0.01	0.02	2836
X-RAY DIFFRACTION	r_gen_planes_other	0.002	0.02	602

LS refinement shell

Resolution: 1.501→1.54 Å / R_factor R_free error: 0 / Total num. of bins used: 20

	R_factor	Num. reflection	% reflection
R_free	0.245	187	-
R_work	0.216	3637	-
all	-	3824	-
obs	-	-	85.7 %

Refinement TLS params.

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

ID	L11 (°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)
1	2.2174	1.0145	-4.8062	6.4224	-9.9914	25.0538	0.1709	-0.3612	0.2596	0.8231	0.0349	-0.2386	-1.7907	0.7272	-0.2058	0.1906	-0.0601	-0.0699	0.2905	-0.0714	0.1571	19.626	9.789	-7.543
2	1.6304	-0.6269	2.0816	3.1361	-5.6679	13.3915	-0.1766	-0.0392	0.1014	0.3069	0.2033	-0.1147	-0.7129	0.3576	-0.0267	0.0575	-0.0192	-0.0409	0.2698	-0.0428	0.115	16.384	8.078	-14.925
3	1.2791	-0.7948	2.5944	1.246	-3.3254	11.2289	-0.1295	-0.0903	0.0774	0.0416	0.0044	-0.0889	-0.1586	0.3158	0.1251	0.0288	-0.006	-0.0359	0.1937	0.0056	0.0792	14.547	4.445	-13.79
4	1.8533	-0.6113	1.8641	0.3161	-1.0081	3.5831	0.0137	0.0259	0.0646	-0.0125	-0.057	0.0005	0.0101	0.3299	0.0433	0.0498	0.0032	-0.0529	0.1164	0.0069	0.1074	5.096	6.698	-25.994
5	2.4011	-0.7987	2.1905	0.4083	-1.1436	3.6017	0.0952	0.1417	-0.0476	-0.0595	-0.0889	0.0126	0.0937	0.2871	-0.0062	0.0484	0.0125	-0.0386	0.0889	0.0121	0.1172	0.904	2.667	-35.229
6	6.6485	-0.9593	1.8177	0.3566	-0.0049	1.1921	0.2358	-0.6713	-0.5072	-0.0445	0.0012	0.0459	0.2563	-0.1412	-0.237	0.153	0.0085	-0.0575	0.2465	0.0798	0.2	2.901	-5.276	-14.579
7	5.282	-3.327	5.7684	3.1807	-3.1636	6.711	-0.1873	-0.4073	-0.257	0.0269	0.3442	0.2214	-0.2821	-0.1195	-0.1569	0.0381	-0.0202	-0.0269	0.4719	0.1123	0.1508	1.355	3.087	-7.404
8	18.9019	-17.62	11.6726	19.1713	-7.5564	11.4291	-0.5468	-1.2788	-0.11	0.4508	0.9101	-0.126	-0.3222	-0.8188	-0.3632	0.0474	0.0932	-0.0287	0.6405	0.1137	0.106	0.888	1.412	-4.814
9	1.367	0.3558	3.391	0.2979	0.442	9.4005	-0.0367	-0.0253	0.098	-0.004	-0.1296	0.0775	-0.1043	0.2635	0.1662	0.0587	-0.0124	-0.0348	0.175	-0.0013	0.106	1.211	7.489	-10.87
10	5.4322	-2.9991	3.3302	3.3216	-1.9526	3.135	0.3402	-0.054	-0.4769	-0.1406	-0.1938	0.121	0.2684	0.176	-0.1464	0.0749	0.0019	-0.0579	0.1071	0.042	0.1757	-0.949	-6.294	-23.089
11	4.1245	-1.9207	1.5912	1.452	-0.9796	1.474	0.0012	-0.0553	-0.1029	0.0138	-0.0607	-0.032	0.0391	0.088	0.0595	0.0657	-0.0009	-0.0353	0.0667	0.0217	0.1245	-4.207	-0.572	-25.37
12	0.0466	-0.1315	-0.2727	1.0379	0.3536	1.9239	-0.0544	0.0429	-0.0354	0.1429	-0.0616	0.157	0.1934	-0.2736	0.116	0.0957	-0.0204	-0.0338	0.1352	-0.0283	0.1715	-17.749	3.847	-33.929
13	13.5137	-1.2901	10.7978	1.3217	-3.1174	12.3042	0.2194	-0.0364	-0.629	-0.183	0.1355	-0.062	0.4819	-0.2792	-0.3549	0.0995	-0.0337	-0.0363	0.0718	-0.0076	0.147	-18.112	-3.755	-40.258
14	0.3085	0.8541	0.4073	2.5679	0.2916	4.5488	0.013	-0.0108	0.0578	0.0131	-0.0075	0.123	0.1681	-0.24	-0.0055	0.0866	-0.0073	-0.051	0.1198	-0.0109	0.1634	-18.903	2.269	-42.042
15	4.8833	-0.6567	2.139	2.3147	0.1218	1.1547	-0.0381	-0.0915	-0.1458	0.0245	0.039	0.0774	-0.085	-0.1075	-0.0008	0.0639	0.0056	-0.0395	0.0976	0.0069	0.1185	-19.821	9.368	-43.765
16	1.5845	0.0781	1.403	0.1289	-0.3709	3.3047	-0.0622	0.0068	0.1954	0.0339	-0.0197	-0.0198	-0.1772	-0.0548	0.0819	0.082	0.0207	-0.0473	0.0733	0.0129	0.149	-12.07	14.321	-39.409
17	2.4398	-1.3277	2.3813	1.3273	-1.9569	3.4507	0.1338	-0.0794	-0.0375	-0.1541	-0.146	-0.0017	0.2103	0.3217	0.0122	0.0683	0.0225	-0.0427	0.2135	0.0336	0.1347	9.705	0.772	-16.081
18	4.3878	-0.888	3.3768	0.2767	-0.7743	3.6473	0.1145	0.2492	-0.1483	-0.0509	-0.0479	0.0138	0.1035	0.359	-0.0667	0.0498	0.0156	-0.0429	0.1005	0.0014	0.1108	2.547	1.519	-34.827
19	4.9792	-2.585	2.4403	1.4389	-1.1612	2.5653	0.196	0.1483	-0.3057	-0.1238	-0.0553	0.1224	0.1711	0.0216	-0.1407	0.0649	0.003	-0.056	0.0644	-0.0059	0.1316	-13.316	2.282	-45.498
20	3.1206	-0.651	2.7121	0.2841	-0.8183	3.5997	-0.0355	0.0624	-0.0584	0.0277	-0.0126	-0.0197	-0.0424	0.3845	0.0481	0.0255	0.0107	-0.0355	0.2529	0.0179	0.0891	16.874	0.715	-23.683
21	4.7808	-0.4545	3.6352	0.2086	-0.2503	5.2193	-0.0255	0.3578	0.1268	-0.0027	-0.1102	-0.0368	-0.2098	0.4384	0.1357	0.0252	0.0021	-0.0308	0.2551	-0.0026	0.0805	16.369	3.472	-30.302

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Auth asym-ID	Auth seq-ID
1	X-RAY DIFFRACTION	1	A	1 - 14
2	X-RAY DIFFRACTION	2	A	15 - 29
3	X-RAY DIFFRACTION	3	A	30 - 45
4	X-RAY DIFFRACTION	4	A	46 - 70
5	X-RAY DIFFRACTION	5	A	71 - 91
6	X-RAY DIFFRACTION	6	A	92 - 107
7	X-RAY DIFFRACTION	7	A	108 - 119
8	X-RAY DIFFRACTION	8	A	120 - 128
9	X-RAY DIFFRACTION	9	A	134 - 148
10	X-RAY DIFFRACTION	10	A	149 - 158
11	X-RAY DIFFRACTION	11	A	159 - 174
12	X-RAY DIFFRACTION	12	A	175 - 181
13	X-RAY DIFFRACTION	13	A	182 - 186
14	X-RAY DIFFRACTION	14	A	187 - 192
15	X-RAY DIFFRACTION	15	A	193 - 199
16	X-RAY DIFFRACTION	16	A	200 - 217
17	X-RAY DIFFRACTION	17	A	218 - 235
18	X-RAY DIFFRACTION	18	A	236 - 258
19	X-RAY DIFFRACTION	19	A	259 - 268
20	X-RAY DIFFRACTION	20	A	269 - 284
21	X-RAY DIFFRACTION	21	A	285 - 301

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