Ligand selectivity hotspots in serotonin GPCRs.
GPCR
drug selectivity
serotonin receptor
structure-activity relationships
Journal
Trends in pharmacological sciences
ISSN: 1873-3735
Titre abrégé: Trends Pharmacol Sci
Pays: England
ID NLM: 7906158
Informations de publication
Date de publication:
Dec 2023
Dec 2023
Historique:
received:
02
09
2023
revised:
20
09
2023
accepted:
28
09
2023
medline:
20
11
2023
pubmed:
2
11
2023
entrez:
1
11
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37914598
pii: S0165-6147(23)00214-6
doi: 10.1016/j.tips.2023.09.012
pii:
doi:
Substances chimiques
Receptors, G-Protein-Coupled
0
Serotonin
333DO1RDJY
Ligands
0
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
978-990Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests D.E.G. has a part-time employment at Kvantify. A.A.J. is co-founder and co-owner of the company Lophora ApS.