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Yorodumi- PDB-8y38: Cryo-EM structure of Staphylococcus aureus 70S ribosome (strain 1... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8y38 | ||||||
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Title | Cryo-EM structure of Staphylococcus aureus 70S ribosome (strain 15B196) in complex with MCX-190. | ||||||
Components |
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Keywords | RIBOSOME / ANTIBIOTIC | ||||||
Function / homology | Function and homology information large ribosomal subunit / ribosomal small subunit assembly / small ribosomal subunit / 5S rRNA binding / transferase activity / cytosolic small ribosomal subunit / ribosomal large subunit assembly / tRNA binding / rRNA binding / ribosome ...large ribosomal subunit / ribosomal small subunit assembly / small ribosomal subunit / 5S rRNA binding / transferase activity / cytosolic small ribosomal subunit / ribosomal large subunit assembly / tRNA binding / rRNA binding / ribosome / structural constituent of ribosome / ribonucleoprotein complex / translation / mRNA binding / zinc ion binding / cytoplasm Similarity search - Function | ||||||
Biological species | Staphylococcus aureus (bacteria) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.58 Å | ||||||
Authors | Li, Y. / Lu, G. / Li, J. / Pei, X. / Lin, J. | ||||||
Funding support | China, 1items
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Citation | Journal: Cell Discov / Year: 2024 Title: Synthetic macrolides overcoming MLSK-resistant pathogens. Authors: Cong-Xuan Ma / Ye Li / Wen-Tian Liu / Yun Li / Fei Zhao / Xiao-Tian Lian / Jing Ding / Si-Meng Liu / Xie-Peng Liu / Bing-Zhi Fan / Li-Yong Liu / Feng Xue / Jian Li / Jue-Ru Zhang / Zhao Xue ...Authors: Cong-Xuan Ma / Ye Li / Wen-Tian Liu / Yun Li / Fei Zhao / Xiao-Tian Lian / Jing Ding / Si-Meng Liu / Xie-Peng Liu / Bing-Zhi Fan / Li-Yong Liu / Feng Xue / Jian Li / Jue-Ru Zhang / Zhao Xue / Xiao-Tong Pei / Jin-Zhong Lin / Jian-Hua Liang / Abstract: Conventional macrolide-lincosamide-streptogramin B-ketolide (MLSK) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation ...Conventional macrolide-lincosamide-streptogramin B-ketolide (MLSK) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation of rRNA base A2058 or its G2058 mutation, while the presence of unmodified A2058 is crucial for high selectivity of traditional MLSK in targeting pathogens over human cells. The absence of effective modes of action reinforces the prevailing belief that constitutively antibiotic-resistant Staphylococcus aureus remains impervious to existing macrolides including telithromycin. Here, we report the design and synthesis of a novel series of macrolides, featuring the strategic fusion of ketolide and quinolone moieties. Our effort led to the discovery of two potent compounds, MCX-219 and MCX-190, demonstrating enhanced antibacterial efficacy against a broad spectrum of formidable pathogens, including A2058-methylated Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and notably, the clinical Mycoplasma pneumoniae isolates harboring A2058G mutations which are implicated in the recent pneumonia outbreak in China. Mechanistic studies reveal that the modified quinolone moiety of MCX-190 establishes a distinctive secondary binding site within the nascent peptide exit tunnel. Structure-activity relationship analysis underscores the importance of this secondary binding, maintained by a sandwich-like π-π stacking interaction and a water-magnesium bridge, for effective engagement with A2058-methylated ribosomes rather than topoisomerases targeted by quinolone antibiotics. Our findings not only highlight MCX-219 and MCX-190 as promising candidates for next-generation MLSK antibiotics to combat antibiotic resistance, but also pave the way for the future rational design of the class of MLSK antibiotics, offering a strategic framework to overcome the challenges posed by escalating antibiotic resistance. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8y38.cif.gz | 3 MB | Display | PDBx/mmCIF format |
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PDB format | pdb8y38.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 8y38.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8y38_validation.pdf.gz | 1.9 MB | Display | wwPDB validaton report |
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Full document | 8y38_full_validation.pdf.gz | 2 MB | Display | |
Data in XML | 8y38_validation.xml.gz | 197.1 KB | Display | |
Data in CIF | 8y38_validation.cif.gz | 350.5 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/y3/8y38 ftp://data.pdbj.org/pub/pdb/validation_reports/y3/8y38 | HTTPS FTP |
-Related structure data
Related structure data | 38875MC 8y36C 8y37C 8y39C 39379 M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
+Large ribosomal subunit protein ... , 28 types, 28 molecules 1234CDEFGHIJKLMNOPQRSTUVWXYZ
-RNA chain , 3 types, 3 molecules ABa
#5: RNA chain | Mass: 946121.188 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: GenBank: 1865318698 |
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#6: RNA chain | Mass: 36974.945 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: GenBank: 1760048038 |
#31: RNA chain | Mass: 500724.594 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: GenBank: 1747281577 |
-Small ribosomal subunit protein ... , 19 types, 19 molecules bcdefghijklmnopqrst
#32: Protein | Mass: 26588.031 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: A0A2X2M020 |
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#33: Protein | Mass: 24143.867 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: P66554 |
#34: Protein | Mass: 23051.416 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: P66564 |
#35: Protein | Mass: 17770.512 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: P66580 |
#36: Protein | Mass: 11613.146 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: P66596 |
#37: Protein | Mass: 17826.555 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: P66617 |
#38: Protein | Mass: 14854.315 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: P66631 |
#39: Protein | Mass: 14642.725 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: P66647 |
#40: Protein | Mass: 11598.503 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: P66335 |
#41: Protein | Mass: 13907.978 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: P66358 |
#42: Protein | Mass: 16813.574 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: A0A133PZQ5 |
#43: Protein | Mass: 13747.919 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: P66389 |
#44: Protein | Mass: 7317.769 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: P66413 |
#45: Protein | Mass: 10634.330 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: Q7A116 |
#46: Protein | Mass: 10253.886 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: P66441 |
#47: Protein | Mass: 10196.888 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: Q8NVB4 |
#48: Protein | Mass: 9332.018 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: P66469 |
#49: Protein | Mass: 12319.340 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: A0A133PYC3 |
#50: Protein | Mass: 9039.472 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Staphylococcus aureus (bacteria) / Strain: 15B196 / References: UniProt: Q7A0R9 |
-Non-polymers , 3 types, 17 molecules
#51: Chemical | ChemComp-A1D6G / Mass: 969.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C50H72N4O15 / Feature type: SUBJECT OF INVESTIGATION | ||
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#52: Chemical | ChemComp-MG / #53: Water | ChemComp-HOH / | |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Staphylococcus aureus 70S ribosome (strain 15B196) in complex with MCX-190. Type: RIBOSOME / Entity ID: #1-#50 / Source: NATURAL |
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Source (natural) | Organism: Staphylococcus aureus (bacteria) / Strain: 15B196 |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 500 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
CTF correction | Type: NONE |
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3D reconstruction | Resolution: 2.58 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 47560 / Symmetry type: POINT |