7qq3
Cryo-EM structure of the E.coli 50S ribosomal subunit in complex with the antibiotic Myxovalargin A.
Structural highlights
FunctionRL2_ECOLI One of the primary rRNA binding proteins. Located near the base of the L1 stalk, it is probably also mobile. Required for association of the 30S and 50S subunits to form the 70S ribosome, for tRNA binding and peptide bond formation. It has been suggested to have peptidyltransferase activity; this is highly controversial.[HAMAP-Rule:MF_01320_B] In the E.coli 70S ribosome in the initiation state it has been modeled to make several contacts with the 16S rRNA (forming bridge B7b, PubMed:12809609); these contacts are broken in the model with bound EF-G.[HAMAP-Rule:MF_01320_B] Publication Abstract from PubMedResistance of bacterial pathogens against antibiotics is declared by WHO as a major global health threat. As novel antibacterial agents are urgently needed, we re-assessed the broad-spectrum myxobacterial antibiotic myxovalargin and found it to be extremely potent against Mycobacterium tuberculosis. To ensure compound supply for further development, we studied myxovalargin biosynthesis in detail enabling production via fermentation of a native producer. Feeding experiments as well as functional genomics analysis suggested a structural revision, which was eventually corroborated by the development of a concise total synthesis. The ribosome was identified as the molecular target based on resistant mutant sequencing, and a cryo-EM structure revealed that myxovalargin binds within and completely occludes the exit tunnel, consistent with a mode of action to arrest translation during a late stage of translation initiation. These studies open avenues for structure-based scaffold improvement toward development as an antibacterial agent. The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition.,Koller TO, Scheid U, Kosel T, Herrmann J, Krug D, Boshoff HIM, Beckert B, Evans JC, Schlemmer J, Sloan B, Weiner DM, Via LE, Moosa A, Ioerger TR, Graf M, Zinshteyn B, Abdelshahid M, Nguyen F, Arenz S, Gille F, Siebke M, Seedorf T, Plettenburg O, Green R, Warnke AL, Ullrich J, Warrass R, Barry CE 3rd, Warner DF, Mizrahi V, Kirschning A, Wilson DN, Muller R J Am Chem Soc. 2023 Jan 18;145(2):851-863. doi: 10.1021/jacs.2c08816. Epub 2023 , Jan 5. PMID:36603206[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
