| Title: | Structure of the class D GPCR Ste2 dimer coupled to two G proteins |
| Author(s): | Velazhahan V; Ma N; Pandy-Szekeres G; Kooistra AJ; Lee Y; Gloriam DE; Vaidehi N; Tate CG; |
| Address: | "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" |
| DOI: | 10.1038/s41586-020-2994-1 |
| ISSN/ISBN: | 1476-4687 (Electronic) 0028-0836 (Print) 0028-0836 (Linking) |
| Abstract: | "G-protein-coupled receptors (GPCRs) are divided phylogenetically into six classes(1,2), 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 function(3). 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 A 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 diseases(4)" |
| Keywords: | "Amino Acid Sequence Binding Sites *Cryoelectron Microscopy GTP-Binding Protein alpha Subunits, Gq-G11/chemistry/metabolism GTP-Binding Protein beta Subunits/chemistry/metabolism GTP-Binding Protein gamma Subunits/chemistry/metabolism Heterotrimeric GTP-Bi;" |
| Notes: | "MedlineVelazhahan, Vaithish Ma, Ning Pandy-Szekeres, Gaspar Kooistra, Albert J Lee, Yang Gloriam, David E Vaidehi, Nagarajan Tate, Christopher G eng MC_U105197215/MRC_/Medical Research Council/United Kingdom MRF_MRF-110-057-S-RADA-C0940/MRF/MRF/United Kingdom R01 GM097261/GM/NIGMS NIH HHS/ R01 GM117923/GM/NIGMS NIH HHS/ Comparative Study England 2020/12/04 Nature. 2021 Jan; 589(7840):148-153. doi: 10.1038/s41586-020-2994-1. Epub 2020 Dec 2" |
