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

Vaithish Velazhahan, Ning Ma, Gáspár Pándy-Szekeres, Albert J. Kooistra, Yang Lee, David E. Gloriam, Nagarajan Vaidehi and Christopher G. Tate ()
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Vaithish Velazhahan: MRC Laboratory of Molecular Biology
Ning Ma: Beckman Research Institute of the City of Hope
Gáspár Pándy-Szekeres: Universitetsparken 2
Albert J. Kooistra: Universitetsparken 2
Yang Lee: MRC Laboratory of Molecular Biology
David E. Gloriam: Universitetsparken 2
Nagarajan Vaidehi: Beckman Research Institute of the City of Hope
Christopher G. Tate: MRC Laboratory of Molecular Biology

Nature, 2021, vol. 589, issue 7840, 148-153

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-020-2994-1

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