Biology subjects

Nury, H.

Publications and source records attributed to Nury, H..

4 recordsLinked to original sources

bioRxiv2025

Structures of the honeybee GABAA RDL receptor illuminate allosteric modulation

Insect GABAA receptors are critical insecticide targets, with all 21st-century commercial compounds acting through a single allosteric membrane site. Here we describe three ligand binding sites and the associated receptor conformations for the honeybee RDL receptor, combining cryo-EM, electrophysiology and molecular dynamics. First the conservation of the GABA site explains the absence of insect-selective orthosteric compounds. Second, the classical modulation site, occupied here by abamectin, exists in a closed-pore conformation contrasting with ivermectin-bound states in other receptors. Third, using the fungal-derived Chrodrimamin B, we resolve an unanticipated membrane modulation pocket structurally analogous yet pharmacologically opposite to a neurosteroid site in mammalian receptors. Structures also reveal the existence of an intersubunit, conformation-dependent, PIP2 lipid site. We foresee our results to be the starting point for investigations on the physiological modulation of insect GABAA receptors. The honeybee receptor structures may also foster the search for environmentally benign insecticides.

biophysics↗

bioRxiv2024

Asynchronous subunit transitions precede acetylcholine receptor activation

Rapid communication at synapses is facilitated by postsynaptic receptors, which convert a chemical signal into an electrical response. In the case of ligand-gated ion channels, agonist binding triggers rapid transition through a series of intermediate states leading to a transient open-pore conformation. These transitions are usually framed in terms of a mechanism where agonist binding and channel activation are separate events. Here, we collect cryo-EM images over a range of agonist concentrations to define structures of the muscle-type nicotinic acetylcholine receptor in unliganded, mono-liganded, and di-liganded states. We show that agonist binding to a single agonist site stabilizes an intermediate state where an entire principal agonist-binding subunit has transitioned to an active-like conformation, while the other unoccupied principal subunit remains inactive, albeit poised for activation. Binding of agonist to the second agonist site fully activates the remaining subunits leading to hydration of the ion pore. Uniting this cryo-EM derived intermediate structure with single-channel recordings leads to a model where individual acetylcholine receptor subunits asynchronously undergo conformational transitions, and thus a sequential activation mechanism that has implications for the entire superfamily of pentameric ligand-gated ion channels.

neuroscience↗

bioRxiv2024

Structural Determinants for Activity of the Antidepressant Vortioxetine at Human and Rodent 5-HT3 receptors

Vortioxetine (VTX) is a recent antidepressant that targets a variety of serotonin receptors. We investigate the drugs molecular mechanism of operation at serotonin 5-HT3 receptors (5-HT3R), which features two mysterious properties: VTX acts differently on rodent and human 5-HT3R; VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HT3R and an agonist bound-like state of the human 5-HT3R, in line with the functional profile of the drug. We report four human 5-HT3R structures and show that the human receptor transmembrane domain is intrinsically fragile. We also explain the lack of recovery after VTX administration via a membrane partition mechanism.

biochemistry↗

bioRxiv2020

The binding of palonosetron and other antiemetic drugs to the serotonin 5-HT3 receptor

Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3 receptor antagonists are the most commonly prescribed class of drugs to control chemotherapy-induced nausea and vomiting (CINV). These antagonists have been clinically successful drugs since the 1980s, yet our understanding of how they operate at the molecular level has been hampered by the difficulty of obtaining structures of drug-receptor complexes. Here, we report the cryo-EM structure of the palonosetron-bound 5-HT3 receptor. We investigate the binding of palonosetron, granisetron, dolasetron, ondansetron, and cilansetron using molecular dynamics, covering the whole set of antagonists used in the clinical practice. The structural and computational results yield detailed atomic insight into the binding modes of the drugs. In light of our data, we establish a comprehensive framework underlying the inhibition mechanism by the -setron drug family.

neuroscience↗