English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

G protein-coupled receptors (GPCRs) must discriminate between hundreds of related signal molecules. In order to better understand how GPCR specificity can arise from a common promiscuous ancestor, we used laboratory evolution to invert the specificity of the  Saccharomyces cerevisiae  mating receptor Ste2. This GPCR normally responds weakly to the pheromone of the related species  Kluyveromyces lactis , though we previously showed that mutation N216S is sufficient to make this receptor promiscuous. Here, we found that three additional substitutions, A265T, Y266F and P290Q, can act together to confer a novel specificity for  K .  lactis  pheromone. Unlike wild-type Ste2, this new variant does not rely on differences in binding affinity to discriminate against its non-preferred ligand. Instead, the mutation P290Q is critical for suppressing the efficacy of the native pheromone. These two alternative methods of ligand discrimination were mapped to specific amino acid positions on the peptide pheromones. Our work demonstrates that changes in ligand efficacy can drive changes in GPCR specificity, thus obviating the need for extensive binding pocket re-modeling.

The directed evolution of ligand specificity in a GPCR and the unequal contributions of efficacy and affinity