Abstract
Serotonin receptor (5-HT3AR) is the most common therapeutic target to manage the nausea and vomiting during cancer therapies and in the treatment of irritable bowel syndrome. Setrons, a class of competitive antagonists, cause functional inhibition of 5-HT3AR in the gastrointestinal tract and brainstem, acting as effective anti-emetic agents. Despite their prevalent use, the molecular mechanisms underlying setron binding and inhibition of 5-HT3AR are not fully understood. Here, we present the structure of granisetron-bound full-length 5-HT3AR solved by single-particle cryo-electron microscopy to 2.92 Å resolution. The reconstruction reveals the orientation of granisetron in the orthosteric site with unambiguous density for interacting sidechains. Molecular dynamics simulations and electrophysiology confirm the granisetron binding orientation and the residues central for ligand recognition. Comparison of granisetron-bound 5-HT3AR with the apo and serotonin-bound structures, reveals key insights into the mechanism underlying 5-HT3AR inhibition.
Highlights
Serotonin receptor (5-HT3AR) is the most common therapeutic target to manage the nausea and vomiting during cancer therapies and in the treatment of irritable bowel syndrome
(5-HT3Rs) both on the vagal afferent nerve in the gut and on the chemoreceptor trigger zone in the brainstem, leading to the pathogenesis of emesis in these patients. 5-HT3Rs belong to the pentameric ligand-gated ion channel superfamily[2] and they mediate excitatory postsynaptic signaling. 5-HT3Rs are expressed either as a homopentamer consisting of subunit A or as heteropentamers of subunit A in combination with other subunits (B, C, D, or E). 5-HT3Rs are widely expressed in both the central and peripheral nervous system, and form a part of the brain–gut circuitry that directly control peristalsis, emetic reflex, and visceral pain perception[3,4,5,6,7,8]
Competitive antagonists bind at the orthosteric site of pentameric ligand-gated ion channel (pLGIC) and inhibit channel function by shifting the equilibrium away from the open state (Fig. 1a)
Summary
Serotonin receptor (5-HT3AR) is the most common therapeutic target to manage the nausea and vomiting during cancer therapies and in the treatment of irritable bowel syndrome. Recent high-resolution structures of 5-HT3AR show the channel in an apo conformation and multiple serotonin-bound conformations. We have solved the structure of the fulllength 5-HT3AR bound to granisetron at 2.92 Å resolution.
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