Nature. 2020 Dec 2. doi: 10.1038/s41586-020-2994-1. | PubMed

Vaithish Velazhahan¹, Ning Ma², Gáspár Pándy-Szekeres^3,4, Albert J Kooistra³, Yang Lee¹, David E Gloriam³, Nagarajan Vaidehi², Christopher G Tate⁵

1. MRC Laboratory of Molecular Biology, Cambridge, UK.
2. Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
3. Department of Drug Design and Pharmacology, Universitetsparken 2, Copenhagen, Denmark.
4. Medicinal Chemistry Research Group, Research Center for Natural Sciences, Budapest, Hungary.
5. MRC Laboratory of Molecular Biology, Cambridge, UK. cgt@mrc-lmb.cam.ac.uk.

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.

Presented By Vaithish Velazhahan | ORCID iD