1.A.69.3.1
Fructose-regulated Ca²⁺/cation channel, Gustatory (fructose) receptor-9, Gr9 (Sato et al., 2011),which has 8 TMSs in a 5 + 2 + 1 TMS arrangement. Gr9 is widely expressed in the central nervous system (CNS), as well as oral sensory organs and is involved in the promotion of feeding behaviors (Mang et al. 2016). GRs play roles in sensing tastants, such as sugars and bitter substances. The BmGr9 silkworm GR is a d-fructose-gated ion channel receptor. Morinaga et al. 2022 presented a structural model for a channel pore and a D-fructose binding site in BmGr9. Since the membrane topology and oligomeric state of BmGr9 appears similar to those of an insect odorant receptor co-receptor, Orco, they constructed a structural model of BmGr9 based on the cryo-EM Orco structure. Their site-directed mutagenesis data suggested that transmembrane region 7 forms channel pore and controls channel gating. This model also suggested that a pocket formed by transmembrane helices 2-4 and 6 binds D-fructose. They determined the potent binding mode of D-fructose. They proposed a conformational change that leads to channel opening upon D-fructose binding (Morinaga et al. 2022).  Structures of BmGr9, a fructose-gated cation channel, in agonist-free and fructose-bound states have been determined (Frank et al. 2023).  BmGr9 forms a tetramer similar to distantly related insect Olfactory Receptors (ORs). Upon fructose binding, BmGr9's ion channel gate opens through helix S7b movements. In contrast to ORs, BmGR9's ligand-binding pocket, shaped by a kinked helix S4 and a shorter extracellular S3-S4 loop, is larger and solvent accessible in both agonist-free and fructose-bound states. Also unlike ORs, fructose binding by BmGr9 involves helix S5 and a binding pocket lined with aromatic and polar residues. Structure-based sequence alignments revealed distinct patterns of ligand-binding pocket residue conservation in GR subfamilies associated with distinct ligand classes (Frank et al. 2023).