10QM

E.coli 50S ribosomal subunit bound to compound 48a

This is a non-PDB format compatible entry.

Summary for 10QM

• Entry DOI: 10.2210/pdb10qm/pdb
• EMDB information: 75389
• Descriptor: 23S ribosomal RNA, Large ribosomal subunit protein uL13, Large ribosomal subunit protein uL14, ... (36 entities in total)
• Functional Keywords: 50s subunit, antibiotic, ribosome
• Biological source: Escherichia coli; More
• Total number of polymer chains: 31
• Total formula weight: 1360986.00

Authors

Raskar, T.,Lee, I. (deposition date: 2026-02-01, release date: 2026-06-10)

Primary citation

Lee, I.J.,Li, Q.,Raskar, T.,Pellegrino, J.,Ecker, A.K.,Howard, S.Y.,Fraser, J.S.,Seiple, I.B.
Structure-based design and synthesis of group A streptogramins that bind to the nascent peptide exit tunnel of the ribosome.
Eur.J.Med.Chem., 316:118947-118947, 2026

PubMed Abstract: Natural products and their derivatives have long served as powerful tools for treating bacterial infections, but the rise of antibiotic resistance threatens their continued effectiveness. Targeted structural modification of existing classes of antibiotics is an effective strategy to overcome resistance and extend clinical utility. The development of group A streptogramins that overcome acetyltransferase resistance, a pervasive resistance mechanism to the class, is an example of successful implementation of this strategy. However, the synthetic chemistry to reach these new analogs was limited in its ability to access modifications at the C4 position on the scaffold, a promising modification site that produced the most potent streptogramin to date. Here, we report the development of a modified route to group A streptogramins that enables access to a broad diversity of functionality at C4. Using cryo-EM data to guide structural modifications, we synthesize several series of C4-modified group A streptogramins with sidechains designed to make binding contacts with the exit tunnel of the ribosome. We identify multiple analogs that are active against multidrug-resistant bacteria, including strains that are resistant to macrolides, β-lactams, vancomycin, and first-generation streptogramins. We structurally characterize the binding of two analogs to the bacterial ribosome, revealing new π-stacking interactions between the C4 sidechain and the non-canonical U1782-U2586 base pair. These findings demonstrate how structure-guided drug design can drive the development of next-generation antibiotics and increase the therapeutic potential of the streptogramin class.

PubMed: 42214237
DOI: 10.1016/j.ejmech.2026.118947

Experimental method

ELECTRON MICROSCOPY (2.49 Å)