Structure of the class D GPCR Ste2 dimer coupled to two G proteins

By V. Velazhahan, Ning Ma, Gáspár Pándy-Szekeres, Albert J. Kooistra, Yang Lee, David E. Gloriam, N. Vaidehi, C. Tate. 2020

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G-protein-coupled receptors (GPCRs) are divided phylogenetically into six classes1,2, denoted A to F. More than 370 structures of vertebrate GPCRs (belonging to classes A, B, C and F) have been determined, leading to a substantial understanding of their function3. By contrast, there are no structures of class D GPCRs, which are found exclusively in fungi where they regulate survival and reproduction. Here we determine the structure of a class D GPCR, the Saccharomyces cerevisiae pheromone receptor Ste2, in an active state coupled to the heterotrimeric G protein Gpa1–Ste4–Ste18. Ste2 was purified as a homodimer coupled to two G proteins. The dimer interface of Ste2 is formed by the N terminus, the transmembrane helices H1, H2 and H7, and the first extracellular loop ECL1. We establish a class D1 generic residue numbering system (CD1) to enable comparisons with orthologues and with other GPCR classes. The structure of Ste2 bears similarities in overall topology to class A GPCRs, but the transmembrane helix H4 is shifted by more than 20 Å and the G-protein-binding site is a shallow groove rather than a cleft. The structure provides a template for the design of novel drugs to target fungal GPCRs, which could be used to treat numerous intractable fungal diseases4. A cryo-electron microscopy structure of the yeast pheromone receptor Ste2, a class D G-protein-coupled receptor, in its active state reveals that Ste2 is a homodimer that couples to two G proteins.

Subfields: Molecular Biology, Spectroscopy

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In Molecular Biology

  1. Albert J. Kooistra
  2. Gáspár Pándy-Szekeres
  3. Alibek Mamyrbekov
  4. György M. Keserü
  5. Jimmy Caroli
  6. Ali A Kermani
  7. David E. Gloriam

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