Structure of the class D GPCR Ste2 dimer coupled to two G proteins
Vaithish Velazhahan1, Ning Ma2, Gáspár Pándy-Szekeres3,4, Albert J Kooistra3, Yang Lee1, David E Gloriam3, Nagarajan Vaidehi2, Christopher G Tate5
- MRC Laboratory of Molecular Biology, Cambridge, UK.
- Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
- Department of Drug Design and Pharmacology, Universitetsparken 2, Copenhagen, Denmark.
- Medicinal Chemistry Research Group, Research Center for Natural Sciences, Budapest, Hungary.
- 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