TY - JOUR
T1 - Orphan G protein-coupled receptors
T2 - the ongoing search for a home
AU - Jobe, Amie
AU - Vijayan, Ranjit
N1 - Publisher Copyright:
Copyright © 2024 Jobe and Vijayan.
PY - 2024
Y1 - 2024
N2 - G protein-coupled receptors (GPCRs) make up the largest receptor superfamily, accounting for 4% of protein-coding genes. Despite the prevalence of such transmembrane receptors, a significant number remain orphans, lacking identified endogenous ligands. Since their conception, the reverse pharmacology approach has been used to characterize such receptors. However, the multifaceted and nuanced nature of GPCR signaling poses a great challenge to their pharmacological elucidation. Considering their therapeutic relevance, the search for native orphan GPCR ligands continues. Despite limited structural input in terms of 3D crystallized structures, with advances in machine-learning approaches, there has been great progress with respect to accurate ligand prediction. Though such an approach proves valuable given that ligand scarcity is the greatest hurdle to orphan GPCR deorphanization, the future pairings of the remaining orphan GPCRs may not necessarily take a one-size-fits-all approach but should be more comprehensive in accounting for numerous nuanced possibilities to cover the full spectrum of GPCR signaling.
AB - G protein-coupled receptors (GPCRs) make up the largest receptor superfamily, accounting for 4% of protein-coding genes. Despite the prevalence of such transmembrane receptors, a significant number remain orphans, lacking identified endogenous ligands. Since their conception, the reverse pharmacology approach has been used to characterize such receptors. However, the multifaceted and nuanced nature of GPCR signaling poses a great challenge to their pharmacological elucidation. Considering their therapeutic relevance, the search for native orphan GPCR ligands continues. Despite limited structural input in terms of 3D crystallized structures, with advances in machine-learning approaches, there has been great progress with respect to accurate ligand prediction. Though such an approach proves valuable given that ligand scarcity is the greatest hurdle to orphan GPCR deorphanization, the future pairings of the remaining orphan GPCRs may not necessarily take a one-size-fits-all approach but should be more comprehensive in accounting for numerous nuanced possibilities to cover the full spectrum of GPCR signaling.
KW - 7TM receptors
KW - GPCR deorphanization
KW - GPCRs
KW - orphan receptors
KW - seven transmembrane receptors
UR - http://www.scopus.com/inward/record.url?scp=85187700269&partnerID=8YFLogxK
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U2 - 10.3389/fphar.2024.1349097
DO - 10.3389/fphar.2024.1349097
M3 - Review article
AN - SCOPUS:85187700269
SN - 1663-9812
VL - 15
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - 1349097
ER -