8b7y
Cryo-EM structure of the E.coli 70S ribosome in complex with the antibiotic Myxovalargin B.
Structural highlights
FunctionRL6_ECOLI This protein binds directly to at least 2 domains of the 23S ribosomal RNA, thus is important in its secondary structure. It is located near the subunit interface in the base of the L7/L12 stalk, and near the tRNA binding site of the peptidyltransferase center.[HAMAP-Rule:MF_01365] Gentamicin-resistant mutations in this protein affect translation fidelity.[HAMAP-Rule:MF_01365] 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. See AlsoReferences
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