TY - JOUR
T1 - Ligand selectivity hotspots in serotonin GPCRs
AU - Simon, Icaro A
AU - Bjørn-Yoshimoto, Walden E
AU - Harpsøe, Kasper
AU - Iliadis, Stylianos
AU - Svensson, Bo
AU - Jensen, Anders A
AU - Gloriam, David E
N1 - Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.
PY - 2023
Y1 - 2023
N2 - Serotonin is a neurotransmitter regulating numerous physiological processes also modulated by drugs, for example, schizophrenia, depression, migraine, and obesity. However, these drugs typically have adverse effects caused by promiscuous binding across 12 serotonin and more than 20 homologous receptors. Recently, structures of the entire serotonin receptor family uncovered molecular ligand recognition. Here, we present a map of 19 'selectivity hotspots', that is, nonconserved binding site residues governing selectivity via favorable target interactions or repulsive 'off-target' contacts. Furthermore, we review functional rationale from observed ligand-binding affinities and mutagenesis effects. Unifying knowledge underlying specific probes and drugs is critical toward the functional characterization of different receptors and alleviation of adverse effects.
AB - Serotonin is a neurotransmitter regulating numerous physiological processes also modulated by drugs, for example, schizophrenia, depression, migraine, and obesity. However, these drugs typically have adverse effects caused by promiscuous binding across 12 serotonin and more than 20 homologous receptors. Recently, structures of the entire serotonin receptor family uncovered molecular ligand recognition. Here, we present a map of 19 'selectivity hotspots', that is, nonconserved binding site residues governing selectivity via favorable target interactions or repulsive 'off-target' contacts. Furthermore, we review functional rationale from observed ligand-binding affinities and mutagenesis effects. Unifying knowledge underlying specific probes and drugs is critical toward the functional characterization of different receptors and alleviation of adverse effects.
U2 - 10.1016/j.tips.2023.09.012
DO - 10.1016/j.tips.2023.09.012
M3 - Review
C2 - 37914598
VL - 44
SP - 978
EP - 990
JO - Trends in Pharmacological Sciences
JF - Trends in Pharmacological Sciences
SN - 0165-6147
IS - 12
ER -