Ribosomal P-protein stalk function is targeted by sordarin antifungals.
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.
Gómez-Lorenzo
M G
MG
Research Department, Glaxo Wellcome, S. A., Severo Ochoa 2, 28760 Tres Cantos, Spain.
García-Bustos
J F
JF
D000595:Amino Acid Sequence; D000818:Animals; D000935:Antifungal Agents / Q000378:metabolism*; D005816:Genetic Complementation Test; D006801:Humans; D007192:Indenes; D008969:Molecular Sequence Data; D009154:Mutation; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors / Q000037:antagonists & inhibitors; D015800:Protozoan Proteins; D012269:Ribosomal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D017386:Sequence Homology, Amino Acid
D000935:Antifungal Agents; D007192:Indenes; C064601:L12E protein, Trypanosoma cruzi; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors; D015800:Protozoan Proteins; D012269:Ribosomal Proteins; C003329:sordarin