6OF1

Crystal structure of the Thermus thermophilus 70S ribosome in complex with dirithromycin and bound to mRNA and A-, P-, and E-site tRNAs at 2.80A resolution

This is a non-PDB format compatible entry.

Summary for 6OF1

• Entry DOI: 10.2210/pdb6of1/pdb
• Descriptor: 23S Ribosomal RNA, 50S ribosomal protein L14, 50S ribosomal protein L15, ... (61 entities in total)
• Functional Keywords: dirithromycin, macrolide, antibiotic, 70s ribosome, inhibitor, nascent peptide exit tunnel, ribosomal protein ul4, ribosome
• Biological source: Escherichia coli; More
• Total number of polymer chains: 112
• Total formula weight: 4573555.65

Authors

Khabibullina, N.F.,Tereshchenkov, A.G.,Komarova, E.S.,Syroegin, E.A.,Shiriaev, D.I.,Paleskava, A.,Kartsev, V.G.,Bogdanov, A.A.,Konevega, A.L.,Dontsova, O.A.,Sergiev, P.V.,Osterman, I.A.,Polikanov, Y.S. (deposition date: 2019-03-28, release date: 2019-04-17, Last modification date: 2025-03-19)

Primary citation

Khabibullina, N.F.,Tereshchenkov, A.G.,Komarova, E.S.,Syroegin, E.A.,Shiriaev, D.I.,Paleskava, A.,Kartsev, V.G.,Bogdanov, A.A.,Konevega, A.L.,Dontsova, O.A.,Sergiev, P.V.,Osterman, I.A.,Polikanov, Y.S.
Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides.
Antimicrob.Agents Chemother., 63:-, 2019

PubMed Abstract: Although macrolides are known as excellent antibacterials, their medical use has been significantly limited due to the spread of bacterial drug resistance. Therefore, it is necessary to develop new potent macrolides to combat the emergence of drug-resistant pathogens. One of the key steps in rational drug design is the identification of chemical groups that mediate binding of the drug to its target and their subsequent derivatization to strengthen drug-target interactions. In the case of macrolides, a few groups are known to be important for drug binding to the ribosome, such as desosamine. Search for new chemical moieties that improve the interactions of a macrolide with the 70S ribosome might be of crucial importance for the invention of new macrolides. For this purpose, here we studied a classic macrolide, dirithromycin, which has an extended (2-methoxyethoxy)-methyl side chain attached to the C-9/C-11 atoms of the macrolactone ring that can account for strong binding of dirithromycin to the 70S ribosome. By solving the crystal structure of the 70S ribosome in complex with dirithromycin, we found that its side chain interacts with the wall of the nascent peptide exit tunnel in an idiosyncratic fashion: its side chain forms a lone pair-π stacking interaction with the aromatic imidazole ring of the His69 residue in ribosomal protein uL4. To our knowledge, the ability of this side chain to form a contact in the macrolide binding pocket has not been reported previously and potentially can open new avenues for further exploration by medicinal chemists developing next-generation macrolide antibiotics active against resistant pathogens.

PubMed: 30936109
DOI: 10.1128/AAC.02266-18

Experimental method

X-RAY DIFFRACTION (2.8 Å)