Novobiocin activates the mating response in yeast through the alpha-pheromone receptor, Ste2p

In a previous publication we reported the isolation of several yeast mutants sensitive to the coumarin drug novobiocin. Here we characterise the wild-type gene (NBS5), obtained by rescuing a novobiocin-sensitive nbs5 strain to natural novobiocin resistance. We show that nbs5 is allelic to the previously characterised gene sst2, conferring super-sensitivity to the mating pheromones. Although nbs5/sst2 cells of both mating types are super-sensitive to the opposite mating pheromone, only cells of mating-type a are sensitive to novobiocin. We show that the entire effect of the drug is mediated through Ste2p, the alpha-pheromone receptor. Thus, novobiocin is a functional agonist of Ste2p, and may identify a potentially useful interaction between coumarin drugs and the family of G-protein-coupled receptors.