8UD7

Crystal structure of the A2058-N6-dimethylated Thermus thermophilus 70S ribosome in complex with cresomycin, mRNA, deacylated A-site tRNAphe, aminoacylated P-site fMet-tRNAmet, and deacylated E-site tRNAphe at 2.70A resolution

This is a non-PDB format compatible entry.

Summary for 8UD7

• Entry DOI: 10.2210/pdb8ud7/pdb
• Descriptor: 23S Ribosomal RNA, 50S ribosomal protein L14, 50S ribosomal protein L15, ... (61 entities in total)
• Functional Keywords: cresomycin, lincosamides, structure-based drug design, antibiotic, resistance, cfr, erm, methylation, a2058, a2503, 23s rrna, 70s ribosome, inhibition of translation, peptidyl transferase center, nascent peptide exit tunnel, ribosome, ribosome-rna complex, ribosome/rna
• Biological source: Escherichia coli; More
• Total number of polymer chains: 112
• Total formula weight: 4568498.22

Authors

Aleksandrova, E.V.,Syroegin, E.A.,Wu, K.J.Y.,Tresco, B.I.C.,Ramkissoon, A.,See, D.N.Y.,Liow, P.,Dittemore, G.A.,Yu, M.,Testolin, G.,Mitcheltree, M.J.,Liu, R.Y.,Svetlov, M.S.,Myers, A.G.,Polikanov, Y.S. (deposition date: 2023-09-28, release date: 2024-02-21, Last modification date: 2024-02-28)

Primary citation

Wu, K.J.Y.,Tresco, B.I.C.,Ramkissoon, A.,Aleksandrova, E.V.,Syroegin, E.A.,See, D.N.Y.,Liow, P.,Dittemore, G.A.,Yu, M.,Testolin, G.,Mitcheltree, M.J.,Liu, R.Y.,Svetlov, M.S.,Polikanov, Y.S.,Myers, A.G.
An antibiotic preorganized for ribosomal binding overcomes antimicrobial resistance.
Science, 383:721-726, 2024

PubMed Abstract: We report the design conception, chemical synthesis, and microbiological evaluation of the bridged macrobicyclic antibiotic cresomycin (CRM), which overcomes evolutionarily diverse forms of antimicrobial resistance that render modern antibiotics ineffective. CRM exhibits in vitro and in vivo efficacy against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains of , , and . We show that CRM is highly preorganized for ribosomal binding by determining its density functional theory-calculated, solution-state, solid-state, and (wild-type) ribosome-bound structures, which all align identically within the macrobicyclic subunits. Lastly, we report two additional x-ray crystal structures of CRM in complex with bacterial ribosomes separately modified by the ribosomal RNA methylases, chloramphenicol-florfenicol resistance (Cfr) and erythromycin-resistance ribosomal RNA methylase (Erm), revealing concessive adjustments by the target and antibiotic that permit CRM to maintain binding where other antibiotics fail.

PubMed: 38359125
DOI: 10.1126/science.adk8013

Experimental method

X-RAY DIFFRACTION (2.55 Å)