Structural basis of ligand specificity and channel activation in an insect gustatory receptor

Gustatory Receptors (GRs) are critical for insect chemosensation and are potentialtargets for controlling pests and disease vectors, making their structural investigation avital step towards such applications. We present structures of Bombyx mori Gr9(BmGr9), a fructose-gated cation channel, in agonist-free and fructose-bound states.BmGr9 forms a tetramer similar to distantly related insect Olfactory Receptors (ORs).Upon fructose binding, BmGr9’s channel gate opens through helix S7b movements. Incontrast to ORs, BmGR9’s ligand-binding pocket, shaped by a kinked helix S4 and ashorter extracellular S3-S4 loop, is larger and solvent accessible in both agonist-freeand fructose-bound states. Also unlike ORs, fructose binding by BmGr9 involves helixS5 and a pocket lined with aromatic and polar residues. Structure-based sequencealignments reveal distinct patterns of ligand-binding pocket residue conservation in GRsubfamilies associated with different ligand classes. These data provide insight into themolecular basis of GR ligand specificity and function.