High-resolution Structures of multiple 5-HT_3AR-setron complexes reveal a novel mechanism of competitive inhibition

Abstract

Serotonin receptors (5-HT3AR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just beginning to emerge. Here, we present high-resolution cryo-EM structures of full-length 5-HT3AR in complex with palonosetron, ondansetron, and alosetron. Each structure reveals a distinct interaction fingerprint between the setron and binding-pocket residues that may underlie their diverse affinities. In addition, setrons elicit varying degrees of conformational change throughout the channel that, quite surprisingly, lie along the channel activation pathway, suggesting a novel mechanism of competitive inhibition.Molecular dynamic simulations were used to assess binding-poses and the drug-target interaction dynamics. Together, this study provides a molecular basis for setron binding affinities and their inhibitory effects.

Duplicated binding site for RIC-3 in 5-Hydroxytryptamine Receptors Subtype 3

“…Amino acids with charged side chains in stick representation with CPK colors (Nitrogen blue, Oxygen red). This illustration uses the cryoEM structure of 5-HT 3A receptor (PDB 6W1J) 1…”

Mechanism of activation and the rewired network: New drug design concepts

“…Proteins act through structural changes and drugs aim to block their action. A competitive drug binding mechanism is powerful since it directly blocks ligand docking 125,157–166 . A noncompetitive drug binding can be powerful by altering the active site shape, leading to the same outcome 167–177 .…”

“…A competitive drug binding mechanism is powerful since it directly blocks ligand docking. 125,[157][158][159][160][161][162][163][164][165][166] A noncompetitive drug binding can be powerful by altering the active site shape, leading to the same outcome. [167][168][169][170][171][172][173][174][175][176][177] These drug actions typically target the active conformation.…”