PDB-6u33: Structure-based discovery of a novel small-molecule inhibitor of ...

ID or keywords:

Entry

Database: PDB / ID: 6u33

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: 1.75 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 21, 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 ...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 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_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	6u33.cif.gz	140.1 KB	Display	PDBx/mmCIF format
PDB format	pdb6u33.ent.gz	108.5 KB	Display	PDB format
PDBx/mmJSON format	6u33.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Summary document	6u33_validation.pdf.gz	422.1 KB	Display	wwPDB validaton report
Full document	6u33_full_validation.pdf.gz	423.7 KB	Display
Data in XML	6u33_validation.xml.gz	14.7 KB	Display
Data in CIF	6u33_validation.cif.gz	21.4 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/u3/6u33 ftp://data.pdbj.org/pub/pdb/validation_reports/u3/6u33	HTTPS FTP

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Related structure data

Related structure data	6u2sC 6u3fC 6u3tC 6u3yC 6u49C 6u4pC 1lkfS C: citing same article (ref.) S: Starting model for refinement
Similar structure data	1lkf-d 1o87-1 1ffh-d 2j45-1 2j46-1 1jpj-d 1ng1-d 2c04-2 2j45-2 3lkf-d 1jpn-1 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

34.3 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)	123.611, 48.732, 66.731
Angle α, β, γ (deg.)	90.000, 120.850, 90.000
Int Tables number	5
Space group name H-M	C121

Components on special symmetry positions

ID	Model	Components
1	1	A-646- 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-NI / NICKEL (II) ION Mass: 58.693 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ni
#3: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 217 / Source method: isolated from a natural source / Formula: H₂O
Has ligand of interest	N

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Experiment

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

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Sample preparation

Crystal	Density Matthews: 2.56 Å³/Da / Density % sol: 51.94 %
Crystal grow	Temperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.5 Details: 12 mg/mL protein in 10 mM sodium acetate, pH 5.4 against reservoir solution of 20% PEG2000 MME, 10 mM nickel chloride, 0.1 M Tris-HCl, pH 8.5

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: NSLS / Beamline: X4C / Wavelength: 0.979 Å
Detector	Type: MAR CCD 165 mm / Detector: CCD / Date: Mar 27, 2012
Radiation	Monochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.979 Å / Relative weight: 1
Reflection	Resolution: 1.75→57.3 Å / Num. obs: 32045 / % possible obs: 92.6 % / Redundancy: 3 % / CC_1/2: 0.984 / R_merge(I) obs: 0.055 / Net I/σ(I): 15.8
Reflection shell	Resolution: 1.75→1.78 Å / Redundancy: 2.3 % / R_merge(I) obs: 0.297 / Mean I/σ(I) obs: 3.7 / Num. unique obs: 1505 / CC_1/2: 0.938 / % possible all: 58.7

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0158	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: 1.75→57.29 Å / Cor.coef. F_o:F_c: 0.962 / Cor.coef. F_o:F_c free: 0.943 / SU B: 4.856 / SU ML: 0.078 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.115 / ESU R Free: 0.116 / Details: U VALUES : WITH TLS ADDED

	R_factor	Num. reflection	% reflection	Selection details
R_free	0.2173	1574	4.9 %	RANDOM
R_work	0.1747	-	-	-
obs	0.1769	30471	92.39 %	-

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å

Displacement parameters

B_iso max: 77.81 Å² / B_iso mean: 28.224 Å² / B_iso min: 14.1 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	0.35 Å²	-0 Å²	-0.02 Å²
2-	-	1.58 Å²	0 Å²
3-	-	-	-1.11 Å²

Refinement step

Cycle: final / Resolution: 1.75→57.29 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	2380	0	1	217	2598
B_iso mean	-	-	35.68	34.12	-
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	2436
X-RAY DIFFRACTION	r_angle_refined_deg	1.875	1.921	3297
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	6.675	5	295
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	41.668	25.512	127
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	14.481	15	416
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	13.093	15	8
X-RAY DIFFRACTION	r_chiral_restr	0.142	0.2	344
X-RAY DIFFRACTION	r_gen_planes_refined	0.01	0.021	1882

LS refinement shell

Resolution: 1.75→1.794 Å / R_factor R_free error: 0

	R_factor	Num. reflection	% reflection
R_free	0.286	65	-
R_work	0.231	1460	-
obs	-	-	59.69 %

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	1.0079	0.8469	-0.2255	2.7057	-3.6258	16.569	-0.0317	-0.0998	-0.0809	0.0085	0.0362	-0.1706	0.367	0.6515	-0.0045	0.0842	0.1096	0.0538	0.2119	-0.0122	0.1508	-9.52	-9.55	1.433
2	1.3006	0.3775	-3.2548	0.7478	-1.6114	13.0862	-0.0848	-0.298	-0.0416	-0.093	0.07	-0.0381	0.291	0.8284	0.0147	0.0386	0.0533	0.0288	0.2361	0.0241	0.0466	-15.456	-7.689	10.309
3	2.247	0.8698	-4.9582	0.7214	-2.4452	12.257	-0.05	-0.2524	-0.0434	-0.0554	0.0343	-0.0346	0.2143	0.569	0.0156	0.0583	0.0298	0.0319	0.1727	-0.0053	0.058	-17.557	-4.496	8.316
4	3.0938	1.4107	-4.563	0.7201	-2.0142	7.1091	0.0079	-0.175	0.0054	-0.0062	-0.0208	0.0084	0.0655	0.2709	0.0129	0.0732	0.0089	0.0399	0.1145	0.0147	0.0837	-29.157	-6.301	18.664
5	2.3992	1.24	-2.7971	0.7589	-1.2152	3.9099	0.108	-0.1974	0.0499	0.0835	-0.0725	0.0008	-0.0985	0.2021	-0.0355	0.0874	0.0084	0.0361	0.1375	0.015	0.1071	-35.546	-1.866	26.361
6	12.7321	4.9442	-3.7286	3.1663	-0.7796	2.5019	0.2173	0.324	0.3996	-0.142	0.0155	0.0251	-0.3138	-0.2519	-0.2328	0.1259	0.0333	0.0482	0.0526	0.0387	0.0413	-29.958	4.141	5.733
7	5.3129	0.7626	-5.4475	0.4725	-1.1081	5.8859	-0.2461	0.3272	-0.2259	-0.1465	0.0344	-0.0217	0.3297	-0.32	0.2117	0.1152	-0.0447	0.0495	0.1836	-0.0296	0.0795	-29.479	-5.269	-0.492
8	8.6436	7.7873	-6.1703	10.1794	-2.5055	7.3565	-0.1399	0.83	0.0966	-0.1605	0.2662	0.0229	0.0643	-1.0324	-0.1263	0.0465	0.0027	-0.0022	0.2847	0.0472	0.0087	-29.735	-3.476	-3.631
9	5.0638	1.1996	-5.5095	1.2509	-1.0904	6.9479	-0.4737	0.189	-0.3428	-0.1418	0.1061	-0.1113	0.481	-0.1533	0.3676	0.0863	-0.031	0.0576	0.1047	-0.0386	0.0858	-30.442	-8.392	3.749
10	2.6067	3.1674	-2.457	6.1922	-1.4365	3.4283	0.0917	-0.0067	0.0739	-0.1404	0.0305	-0.0501	-0.2554	-0.062	-0.1222	0.0827	0.0451	0.0546	0.1484	0.0117	0.1104	-35.277	5.465	13.153
11	9.2304	4.8758	-4.5707	2.8154	-2.2055	3.0089	-0.0105	0.0289	0.0964	-0.0742	-0.0329	0.0158	-0.0936	-0.1697	0.0434	0.0762	0.0108	0.0262	0.1147	0.0086	0.0737	-38.454	-0.068	15.407
12	3.6631	3.5921	3.1013	5.9982	0.8838	4.5965	0.0109	-0.1065	0.2095	-0.0899	0.0312	0.4202	0.066	-0.3892	-0.0421	0.0277	0.039	0.0335	0.4105	0.0017	0.1272	-53.105	-4.862	21.416
13	12.2408	-3.4938	-4.6113	9.5429	-2.7162	10.9403	0.6229	0.231	0.3894	0.0226	-0.1632	0.0278	-0.7201	-0.3873	-0.4597	0.0577	0.0326	0.0389	0.1697	-0.0198	0.0867	-55.454	3.227	26.998
14	0.9455	-1.352	-2.0652	2.5233	2.7201	4.6082	0.0172	0.1511	-0.0443	-0.1318	0.0086	0.3399	0.0087	-0.384	-0.0258	0.0859	-0.0218	-0.0041	0.3163	0.0186	0.2071	-56.134	-2.677	29.164
15	6.4703	1.8231	-3.9112	3.9324	-0.6592	2.4419	-0.2928	0.4686	-0.0818	-0.0882	0.1851	0.0578	0.2081	-0.3001	0.1077	0.0998	-0.0194	0.0521	0.2592	-0.0337	0.1243	-56.73	-9.703	31.248
16	1.8124	0.8718	-1.7833	1.2016	-0.0631	2.574	-0.1632	0.0124	-0.2052	-0.0319	-0.0389	-0.0907	0.2275	-0.086	0.2021	0.094	-0.0262	0.0607	0.1167	0.0113	0.1188	-47.978	-14.291	29.253
17	4.9643	2.5857	-4.7466	2.1267	-2.6285	5.9516	0.1071	-0.2314	0.0852	-0.0479	-0.0655	0.0142	-0.0859	0.458	-0.0416	0.0812	-0.0105	0.0492	0.1452	0.0078	0.0838	-23.164	-0.802	9.175
18	3.5787	0.9201	-3.5224	0.6288	-0.6843	3.9887	0.1038	-0.2083	0.1703	0.0279	-0.001	0.0261	-0.0954	0.2271	-0.1028	0.0627	0.0009	0.0316	0.1578	0.0096	0.0739	-33.955	-0.376	26.02
19	5.8405	3.5601	-1.5908	2.6966	-0.6241	2.1708	0.0514	0.2173	0.3964	0.0814	0.0598	0.2315	-0.1058	-0.2337	-0.1111	0.0557	0.0346	0.0482	0.1429	0.0234	0.0866	-51.355	-1.814	33.737
20	6.4211	-0.0611	-4.2524	0.3294	0.3885	4.8965	-0.0274	-0.3417	0.0125	0.0077	0.1129	-0.0644	-0.0989	0.6457	-0.0855	0.0256	-0.027	0.0284	0.2669	-0.0252	0.0666	-17.602	0.807	17.952
21	7.3195	0.8694	-2.2406	0.3885	0.4606	5.1454	0.0142	-0.7699	-0.4339	0.0153	-0.0755	-0.1162	-0.1802	0.603	0.0614	0.0541	-0.0135	0.0256	0.4847	-0.0073	0.0972	-17.78	-0.722	23.349

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Auth asym-ID	Auth seq-ID
1	X-RAY DIFFRACTION	1	A	4 - 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 - 129
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 - 299

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