TY - JOUR

T1 - Structure of the class D GPCR Ste2 dimer coupled to two G proteins

AU - Velazhahan, Vaithish

AU - Ma, Ning

AU - Pandy-Szekeres, Gaspar

AU - Kooistra, Albert J.

AU - Lee, Yang

AU - Gloriam, David E.

AU - Vaidehi, Nagarajan

AU - Tate, Christopher G.

PY - 2021

Y1 - 2021

N2 - 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 angstrom 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).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.

AB - 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 angstrom 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).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.

KW - ALPHA-FACTOR RECEPTOR

KW - NUCLEOTIDE-BINDING PROTEIN

KW - DUAL LIPID MODIFICATION

KW - SACCHAROMYCES-CEREVISIAE

KW - MOLECULAR SIMULATION

KW - PHEROMONE RECEPTOR

KW - ROLES

KW - SOFTWARE

KW - DYNAMICS

KW - MODEL

U2 - 10.1038/s41586-020-2994-1

DO - 10.1038/s41586-020-2994-1

M3 - Journal article

C2 - 33268889

VL - 589

SP - 148-153 +app 24 pp

JO - Nature

JF - Nature

SN - 0028-0836

ER -