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- PDB-6u4p: Structure-based discovery of a novel small-molecule inhibitor of ... -

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Basic information

Entry
Database: PDB / ID: 6u4p
TitleStructure-based discovery of a novel small-molecule inhibitor of methicillin-resistant S. aureus
ComponentsAlpha-hemolysin
KeywordsTOXIN / alpha-toxin / PVL / Leukocidins / MRSA
Function / homology
Function and homology information


cytolysis in another organism / The NLRP3 inflammasome / Purinergic signaling in leishmaniasis infection / toxin activity / extracellular region / identical protein binding
Similarity search - Function
Aerolysin/haemolysin toxin, conserved site / Aerolysin type toxins signature. / Leukocidin/porin MspA / Leukocidin-like / Bi-component toxin, staphylococci / Leukocidin/Hemolysin toxin / Leukocidin/Hemolysin toxin family / Leukocidin/porin MspA superfamily / Distorted Sandwich / Mainly Beta
Similarity search - Domain/homology
fos-choline-14 / Alpha-hemolysin
Similarity search - Component
Biological speciesStaphylococcus aureus (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.49 Å
AuthorsLiu, J. / Kozhaya, L. / Torres, V.J. / Unutmaz, D. / Lu, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI) United States
CitationJournal: 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
DepositionAug 26, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 25, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 1, 2020Group: 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 1.2May 13, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 11, 2023Group: 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Alpha-hemolysin
B: Alpha-hemolysin
C: Alpha-hemolysin
D: Alpha-hemolysin
E: Alpha-hemolysin
F: Alpha-hemolysin
G: Alpha-hemolysin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)241,05854
Polymers232,5617
Non-polymers8,49747
Water2,054114
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area48500 Å2
ΔGint-511 kcal/mol
Surface area78810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)151.174, 134.616, 130.697
Angle α, β, γ (deg.)90.000, 91.840, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14A
24E
15A
25F
16A
26G
17B
27C
18B
28D
19B
29E
110B
210F
111B
211G
112C
212D
113C
213E
114C
214F
115C
215G
116D
216E
117D
217F
118D
218G
119E
219F
120E
220G
121F
221G

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: ALA / Beg label comp-ID: ALA / End auth comp-ID: ASN / End label comp-ID: ASN / Refine code: _ / Auth seq-ID: 1 - 293 / Label seq-ID: 1 - 293

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13AA
23DD
14AA
24EE
15AA
25FF
16AA
26GG
17BB
27CC
18BB
28DD
19BB
29EE
110BB
210FF
111BB
211GG
112CC
212DD
113CC
213EE
114CC
214FF
115CC
215GG
116DD
216EE
117DD
217FF
118DD
218GG
119EE
219FF
120EE
220GG
121FF
221GG

NCS ensembles :
ID
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21

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Components

#1: Protein
Alpha-hemolysin / Alpha-HL / Alpha-toxin


Mass: 33222.930 Da / Num. of mol.: 7 / Fragment: UNP residues 27-319
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Staphylococcus aureus (bacteria) / Gene: hly, hla / Production host: Escherichia coli K-12 (bacteria) / References: UniProt: P09616
#2: Chemical
ChemComp-PQJ / fos-choline-14 / tetradecyl 2-(trimethyl-$l^{4}-azanyl)ethyl hydrogen phosphate


Mass: 380.523 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C19H43NO4P / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical...
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 33 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 114 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.86 Å3/Da / Density % sol: 56.96 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.2
Details: 10 mg/mL protein in 10 mM sodium acetate, pH 5.4, 25 mM Fos-Choline-14, 40 mM beta-OG against reservoir solution of 1.9 M ammonium sulfate, 0.25 M potassium sodium tartrate, 0.1 M sodium citrate, pH 5.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 17, 2018
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.49→37.8 Å / Num. obs: 87452 / % possible obs: 96.5 % / Redundancy: 3.4 % / CC1/2: 0.968 / Rmerge(I) obs: 0.061 / Net I/σ(I): 10.2
Reflection shellResolution: 2.49→2.56 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.515 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 6406 / CC1/2: 0.864 / % possible all: 98.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 6U49

6u49


Resolution: 2.49→37.8 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.914 / SU B: 23.143 / SU ML: 0.234 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.56 / ESU R Free: 0.288 / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2495 4257 4.9 %RANDOM
Rwork0.2121 ---
obs0.2139 83195 96.2 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 234.72 Å2 / Biso mean: 75.524 Å2 / Biso min: 41.65 Å2
Baniso -1Baniso -2Baniso -3
1--0.6 Å20 Å20.65 Å2
2---1.97 Å2-0 Å2
3---2.53 Å2
Refinement stepCycle: final / Resolution: 2.49→37.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms16380 0 320 114 16814
Biso mean--111.35 60.01 -
Num. residues----2051
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.01217010
X-RAY DIFFRACTIONr_angle_refined_deg1.9881.65523068
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.21252044
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.81724.048882
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.908152940
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9461570
X-RAY DIFFRACTIONr_chiral_restr0.1440.22219
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212852
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A90680.06
12B90680.06
21A90760.06
22C90760.06
31A90320.07
32D90320.07
41A90560.06
42E90560.06
51A90190.06
52F90190.06
61A90370.06
62G90370.06
71B91220.06
72C91220.06
81B90480.07
82D90480.07
91B90690.07
92E90690.07
101B91010.06
102F91010.06
111B91090.06
112G91090.06
121C90700.06
122D90700.06
131C91180.06
132E91180.06
141C91260.06
142F91260.06
151C91370.05
152G91370.05
161D89940.07
162E89940.07
171D90770.06
172F90770.06
181D90590.06
182G90590.06
191E91090.06
192F91090.06
201E90560.07
202G90560.07
211F90920.06
212G90920.06
LS refinement shellResolution: 2.495→2.56 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.372 340 -
Rwork0.289 6066 -
all-6406 -
obs--95.67 %
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)
10.59940.03840.15620.25950.00280.3914-0.00530.27180.1049-0.0632-0.0513-0.01-0.03350.12320.05660.08680.0237-0.10810.47920.08390.2022-11.42149.48423.055
20.25350.06450.20030.26960.13720.32180.07960.1931-0.075-0.08940.00020.00030.06310.1301-0.07980.11040.0666-0.09610.51130.00550.1474-10.19826.72121.914
30.57760.06560.17140.28320.04770.19560.07970.1391-0.1348-0.04460.00780.02770.10970.0292-0.08750.14190.0344-0.15750.3798-0.04770.2105-22.00111.07233.352
40.53230.00720.01780.171-0.04030.10670.0471-0.0194-0.1106-0.0225-0.02370.03440.0764-0.0992-0.02330.1441-0.0552-0.15820.33080.00370.2424-38.11114.38949.032
50.5191-0.1020.04090.2074-0.08530.0847-0.0032-0.1251-0.0122-0.02470.00350.08180.0126-0.1219-0.00030.0752-0.0474-0.1310.359-0.00770.2627-46.41534.05757.144
60.3386-0.15350.15280.2397-0.03280.2873-0.0786-0.02910.137-0.0194-0.00710.0869-0.0539-0.05420.08570.07110.0108-0.14990.3594-0.03140.3277-40.5755.17251.346
70.20860.11320.06040.4245-0.02590.2881-0.05810.13720.188-0.0403-0.03240.0359-0.07250.0240.09050.07850.0302-0.14530.37640.03330.3396-24.96762.21536.248
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 293
2X-RAY DIFFRACTION2B1 - 293
3X-RAY DIFFRACTION3C1 - 293
4X-RAY DIFFRACTION4D1 - 293
5X-RAY DIFFRACTION5E1 - 293
6X-RAY DIFFRACTION6F1 - 293
7X-RAY DIFFRACTION7G1 - 293

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