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J Biol Chem, Vol. 274, Issue 8, 4869-4875, February 19, 1999
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From the The natural product sordarin, a tetracyclic
diterpene glycoside, selectively inhibits fungal protein synthesis by
impairing the function of eukaryotic elongation factor 2 (eEF2).
Sordarin and its derivatives bind to the eEF2-ribosome-nucleotide
complex in sensitive fungi, stabilizing the post-translocational GDP
form. We have previously described a class of Saccharomyces
cerevisiae mutants that exhibit resistance to varying levels of
sordarin and have identified amino acid substitutions in yeast eEF2
that confer sordarin resistance. We now report on a second class of sordarin-resistant mutants. Biochemical and molecular genetic analysis
of these mutants demonstrates that sordarin resistance is dependent on
the essential large ribosomal subunit protein L10e in S. cerevisiae. Five unique L10e alleles were characterized and
sequenced, and several nucleotide changes that differ from the
wild-type sequence were identified. Changes that result in the
resistance phenotype map to 4 amino acid substitutions and 1 amino acid
deletion clustered in a conserved 10-amino acid region of L10e.
Like the previously identified eEF2 mutations, the mutant ribosomes
show reduced sordarin-conferred stabilization of the eEF2-nucleotide-ribosome complex. To our knowledge, this report provides the first description of ribosomal protein mutations affecting
translocation. These results and our previous observations with eEF2
suggest a functional linkage between L10e and eEF2.
Department of Basic Animal Science Research,
Merck Research Laboratories, Rahway, New Jersey 07065 and
§ Wesleyan University, Middletown, Connecticut 06459
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