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Yorodumi- EMDB-38876: cryo-EM structure of Staphylococcus aureus(ATCC 29213) 70S riboso... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-38876 | |||||||||
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Title | cryo-EM structure of Staphylococcus aureus(ATCC 29213) 70S ribosome in complex with MCX-190. | |||||||||
Map data | ||||||||||
Sample |
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Keywords | antibiotic / ribosome / MLSBK-resistant | |||||||||
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 | single particle reconstruction / cryo EM / Resolution: 3.6 Å | |||||||||
Authors | Li Y / Lu G / Li J / Pei X / Lin J | |||||||||
Funding support | China, 1 items
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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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_38876.map.gz | 338.7 MB | EMDB map data format | |
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Header (meta data) | emd-38876-v30.xml emd-38876.xml | 68.5 KB 68.5 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_38876_fsc.xml | 17.1 KB | Display | FSC data file |
Images | emd_38876.png | 232.4 KB | ||
Masks | emd_38876_msk_1.map | 421.9 MB | Mask map | |
Filedesc metadata | emd-38876.cif.gz | 13 KB | ||
Others | emd_38876_half_map_1.map.gz emd_38876_half_map_2.map.gz | 338.1 MB 339.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-38876 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-38876 | HTTPS FTP |
-Validation report
Summary document | emd_38876_validation.pdf.gz | 1.2 MB | Display | EMDB validaton report |
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Full document | emd_38876_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | emd_38876_validation.xml.gz | 24.7 KB | Display | |
Data in CIF | emd_38876_validation.cif.gz | 32.7 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-38876 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-38876 | HTTPS FTP |
-Related structure data
Related structure data | 8y39MC 8y36C 8y37C 8y38C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_38876.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.824 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_38876_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_38876_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_38876_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
+Entire : Staphylococcus aureus(ATCC 29213) 70S ribosome in complex with MC...
+Supramolecule #1: Staphylococcus aureus(ATCC 29213) 70S ribosome in complex with MC...
+Macromolecule #1: 23S ribosomal RNA
+Macromolecule #2: 5S ribosomal RNA
+Macromolecule #31: 16S ribosomal RNA
+Macromolecule #3: Large ribosomal subunit protein uL2
+Macromolecule #4: Large ribosomal subunit protein uL3
+Macromolecule #5: Large ribosomal subunit protein uL4
+Macromolecule #6: Large ribosomal subunit protein uL5
+Macromolecule #7: Large ribosomal subunit protein uL6
+Macromolecule #8: Large ribosomal subunit protein uL13
+Macromolecule #9: Large ribosomal subunit protein uL14
+Macromolecule #10: Large ribosomal subunit protein uL15
+Macromolecule #11: Large ribosomal subunit protein uL16
+Macromolecule #12: Large ribosomal subunit protein bL17
+Macromolecule #13: Large ribosomal subunit protein uL18
+Macromolecule #14: Large ribosomal subunit protein bL19
+Macromolecule #15: Large ribosomal subunit protein bL20
+Macromolecule #16: Large ribosomal subunit protein bL21
+Macromolecule #17: Large ribosomal subunit protein uL22
+Macromolecule #18: Large ribosomal subunit protein uL23
+Macromolecule #19: Large ribosomal subunit protein uL24
+Macromolecule #20: Large ribosomal subunit protein bL25
+Macromolecule #21: Large ribosomal subunit protein bL27
+Macromolecule #22: Large ribosomal subunit protein bL28
+Macromolecule #23: Large ribosomal subunit protein uL29
+Macromolecule #24: Large ribosomal subunit protein uL30
+Macromolecule #25: Large ribosomal subunit protein bL31B
+Macromolecule #26: Large ribosomal subunit protein bL32
+Macromolecule #27: Large ribosomal subunit protein bL33B
+Macromolecule #28: Large ribosomal subunit protein bL34
+Macromolecule #29: Large ribosomal subunit protein bL35
+Macromolecule #30: Large ribosomal subunit protein bL36
+Macromolecule #32: Small ribosomal subunit protein uS2
+Macromolecule #33: Small ribosomal subunit protein uS3
+Macromolecule #34: Small ribosomal subunit protein uS4
+Macromolecule #35: Small ribosomal subunit protein uS5
+Macromolecule #36: Small ribosomal subunit protein bS6
+Macromolecule #37: Small ribosomal subunit protein uS7
+Macromolecule #38: Small ribosomal subunit protein uS8
+Macromolecule #39: Small ribosomal subunit protein uS9
+Macromolecule #40: Small ribosomal subunit protein uS10
+Macromolecule #41: Small ribosomal subunit protein uS11
+Macromolecule #42: Small ribosomal subunit protein uS12
+Macromolecule #43: Small ribosomal subunit protein uS13
+Macromolecule #44: Small ribosomal subunit protein uS14B
+Macromolecule #45: Small ribosomal subunit protein uS15
+Macromolecule #46: Small ribosomal subunit protein bS16
+Macromolecule #47: Small ribosomal subunit protein uS17
+Macromolecule #48: Small ribosomal subunit protein bS18
+Macromolecule #49: Small ribosomal subunit protein uS19
+Macromolecule #50: Small ribosomal subunit protein bS20
+Macromolecule #51: 7-[4-[3-[[(1~{S},2~{R},5~{R},6~{S},7~{S},8~{R},9~{R},11~{R},13~{R...
+Macromolecule #52: MAGNESIUM ION
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |