Ribosomal P-protein Stalk Function Is Targeted by Sordarin Antifungals

• Published in: The Journal of biological chemistry Vol. 273; no. 39; pp. 25041 - 25044
• Main Authors: Lorenzo, MGG, Bustos, JFG
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.09.1998; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Sequence; Animals; Antifungal Agents - metabolism; ANTIMETABOLITES; BINDING; BINDING SITES; DRUGS; Genetic Complementation Test; Humans; Indenes; Molecular Sequence Data; MUTANTS; Mutation; Peptide Elongation Factor 2; Peptide Elongation Factors - antagonists & inhibitors; PROTEIN SYNTHESIS; PROTEINS; Protozoan Proteins; RESISTANCE TO CHEMICALS; RIBOSOMAL PROTEINS; Ribosomal Proteins - chemistry; Ribosomal Proteins - genetics; Ribosomal Proteins - metabolism; RIBOSOMES; SACCHAROMYCES CEREVISIAE; Saccharomyces cerevisiae - genetics; Sequence Homology, Amino Acid; TRANSLATION; TRANSLATION ELONGATION
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.39.25041

Sordarin derivatives are remarkably selective inhibitors of fungal protein synthesis. Available evidence points to a binding site for these inhibitors on elongation factor 2, but high affinity binding requires the presence of ribosomes. The gene mutated in one of the two isolated complementation groups of Saccharomyces cerevisiae mutants resistant to the sordarin derivative GM193663 has now been identified. It is RPP0, encoding the essential protein of the large ribosomal subunit stalk rpP0. Resistant mutants are found to retain most of the binding capacity for the drug, indicating that mutations in rpP0 endow the ribosome with the capacity to perform translation elongation in the presence of the inhibitor. Other proteins of the ribosomal stalk influence the expression of resistance, pointing to a wealth of interactions between stalk components and elongation factors. The involvement of multiple elements of the translation machinery in the mode of action of sordarin antifungals may explain the large selectivity of these compounds, even though the individual target components are highly conserved proteins.