The Binding of Palonosetron and Other Antiemetic Drugs to the Serotonin 5-HT3 Receptor

Abstract

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.

Tapping into 5-HT3 Receptors to Modify Metabolic and Immune Responses

“…The structure of the mouse homologous 5-HT 3 A receptor revealed through crystallography [ 139 ] and cryo-electron micrography [ 140 , 141 , 142 , 143 , 144 , 145 , 146 ] provides considerable insight into 5-HT 3 receptors and is reviewed [ 20 , 147 ]. The mouse A subunit shares 95% homology with the human A subunit, so these studies are readily translatable.…”

“…The Cys-loop is located in the N-terminal region of the extracellular domain where cysteine and proline residues contribute to receptor conformation [ 148 , 149 ]. High-resolution structural studies have been particularly revealing about the extracellular and transmembrane domains of the homomeric receptor [ 140 , 141 , 142 , 143 , 144 , 145 , 146 ]. The extracellular N-terminal region contains the orthosteric ligand binding site that is created between two A subunits asymmetrically arranged to form the A+A- interface [ 141 , 142 , 143 , 144 , 145 , 146 , 147 ] ( Figure 2 A).…”

“…High-resolution structural studies have been particularly revealing about the extracellular and transmembrane domains of the homomeric receptor [ 140 , 141 , 142 , 143 , 144 , 145 , 146 ]. The extracellular N-terminal region contains the orthosteric ligand binding site that is created between two A subunits asymmetrically arranged to form the A+A- interface [ 141 , 142 , 143 , 144 , 145 , 146 , 147 ] ( Figure 2 A). The structural studies have, to a large degree, refined and elaborated on the molecular understanding of the orthosteric sites initially characterized through mutagenesis and ligand binding approaches [ 15 , 19 , 150 , 151 ].…”

“…The structural studies have, to a large degree, refined and elaborated on the molecular understanding of the orthosteric sites initially characterized through mutagenesis and ligand binding approaches [ 15 , 19 , 150 , 151 ]. The three-dimensional structures open up many opportunities to employ additional techniques such as molecular dynamics simulations [ 141 , 142 , 145 , 146 ] in conjunction with photo-crosslinking and mass spectrometry to delve further into the dynamics of ligand receptor interactions [ 152 ]. The transmembrane domains are arranged asymmetrically so transmembrane domain 2 (TM2) faces the pore and contributes most to ion interactions therein ( Figure 2 ).…”

“…All known agonists and competitive antagonists bind at the orthosteric binding site in the extracellular N-terminal region, at the interface between two A subunits [ 15 , 19 , 141 , 142 , 143 , 145 , 151 ]. The competitive antagonists tend to be larger than agonists and are mainly represented by the setron family but include morphine and cocaine [ 3 , 8 , 18 , 22 , 151 ].…”