8G2D

Crystal structure of the wild-type Thermus thermophilus 70S ribosome in complex with tylosin, mRNA, deacylated A- and E-site tRNAphe, and deacylated P-site tRNAmet at 2.70A resolution

This is a non-PDB format compatible entry.

Summary for 8G2D

• Entry DOI: 10.2210/pdb8g2d/pdb
• Descriptor: 23S Ribosomal RNA, 50S ribosomal protein L14, 50S ribosomal protein L15, ... (61 entities in total)
• Functional Keywords: cfr, methyltransferase, multidrug, antibiotic, resistance, methylation, a2503, 23s rrna, 70s ribosome, inhibition of translation, peptidyl transferase center, nascent peptide exit tunnel, iboxamycin, tylosin, ribosome
• Biological source: Escherichia coli; More
• Total number of polymer chains: 112
• Total formula weight: 4572026.88

Authors

Aleksandrova, E.V.,Wu, K.J.Y.,Tresco, B.I.C.,Syroegin, E.A.,Killeavy, E.E.,Balasanyants, S.M.,Svetlov, M.S.,Gregory, S.T.,Atkinson, G.C.,Myers, A.G.,Polikanov, Y.S. (deposition date: 2023-02-03, release date: 2023-12-27, Last modification date: 2024-07-10)

Primary citation

Aleksandrova, E.V.,Wu, K.J.Y.,Tresco, B.I.C.,Syroegin, E.A.,Killeavy, E.E.,Balasanyants, S.M.,Svetlov, M.S.,Gregory, S.T.,Atkinson, G.C.,Myers, A.G.,Polikanov, Y.S.
Structural basis of Cfr-mediated antimicrobial resistance and mechanisms to evade it.
Nat.Chem.Biol., 20:867-876, 2024

PubMed Abstract: The bacterial ribosome is an essential drug target as many clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent resistance mechanisms to PTC-acting drugs in Gram-positive bacteria is C8-methylation of the universally conserved A2503 nucleobase by Cfr methylase in 23S ribosomal RNA. Despite its clinical importance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. Here, we report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-transfer RNAs. These structures reveal an allosteric rearrangement of nucleotide A2062 upon Cfr-mediated methylation of A2503 that likely contributes to the reduced potency of some PTC inhibitors. Additionally, we provide the structural bases behind two distinct mechanisms of engaging the Cfr-methylated ribosome by the antibiotics iboxamycin and tylosin.

PubMed: 38238495
DOI: 10.1038/s41589-023-01525-w

Experimental method

X-RAY DIFFRACTION (2.7 Å)