Structural Studies of Serotonin Receptor Family

Overview

Journal BMB Rep

Specialties Biochemistry
Molecular Biology

Date 2023 Oct 11

PMID 37817438

Authors

Apeksha Parajulee

Kuglae Kim

Affiliations

Soon will be listed here.

Abstract

Serotonin receptors, also known as 5-HT receptors, belong to the G protein-coupled receptors (GPCRs) superfamily. They mediate the effects of serotonin, a neurotransmitter that plays a key role in a wide range of functions including mood regulation, cognition and appetite. The functions of serotonin are mediated by a family of 5-HT receptors including 12 GPCRs belonging to six major families: 5-HT, 5-HT, 5-HT, 5-HT, 5-HT and 5-HT. Despite their distinct characteristics and functions, these receptors' subtypes share common structural features and signaling mechanisms. Understanding the structure, functions and pharmacology of the serotonin receptor family is essential for unraveling the complexities of serotonin signaling and developing targeted therapeutics for neuropsychiatric disorders. However, developing drugs that selectively target specific receptor subtypes is challenging due to the structural similarities in their orthosteric binding sites. This review focuses on the recent advancements in the structural studies of 5-HT receptors, highlighting the key structural features of each subtype and shedding light on their potential as targets for mental health and neurological disorders (such as depression, anxiety, schizophrenia, and migraine) drugs. [BMB Reports 2023; 56(10): 527-536].

Citing Articles

Allosteric Modulators of Serotonin Receptors: A Medicinal Chemistry Survey.

Brunetti L, Francavilla F, Leopoldo M, Lacivita E Pharmaceuticals (Basel). 2024; 17(6).

PMID: 38931362 PMC: 11206742. DOI: 10.3390/ph17060695.

References

Tan Y, Xu P, Huang S, Yang G, Zhou F, He X . Structural insights into the ligand binding and G coupling of serotonin receptor 5-HT. Cell Discov. 2022; 8(1):50. PMC: 9130316. DOI: 10.1038/s41421-022-00412-3. View

Chun L, Zhang W, Liu J . Structure and ligand recognition of class C GPCRs. Acta Pharmacol Sin. 2012; 33(3):312-23. PMC: 4077135. DOI: 10.1038/aps.2011.186. View

Wacker D, Wang S, McCorvy J, Betz R, Venkatakrishnan A, Levit A . Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell. 2017; 168(3):377-389.e12. PMC: 5289311. DOI: 10.1016/j.cell.2016.12.033. View

Kaplan A, Strachan R, Braz J, Craik V, Slocum S, Mangano T . Structure-Based Design of a Chemical Probe Set for the 5-HT Serotonin Receptor. J Med Chem. 2022; 65(5):4201-4217. PMC: 9116900. DOI: 10.1021/acs.jmedchem.1c02031. View

Rasmussen S, Choi H, Rosenbaum D, Kobilka T, Thian F, Edwards P . Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature. 2007; 450(7168):383-7. DOI: 10.1038/nature06325. View

Gumpper R, Fay J, Roth B . Molecular insights into the regulation of constitutive activity by RNA editing of 5HT serotonin receptors. Cell Rep. 2022; 40(7):111211. PMC: 9422347. DOI: 10.1016/j.celrep.2022.111211. View

Roth B, Sheffler D, Kroeze W . Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov. 2004; 3(4):353-9. DOI: 10.1038/nrd1346. View

Thomas D . 5-ht5A receptors as a therapeutic target. Pharmacol Ther. 2006; 111(3):707-14. DOI: 10.1016/j.pharmthera.2005.12.006. View

Peng Y, McCorvy J, Harpsoe K, Lansu K, Yuan S, Popov P . 5-HT Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology. Cell. 2018; 172(4):719-730.e14. PMC: 6309861. DOI: 10.1016/j.cell.2018.01.001. View

10.

Michino M, Beuming T, Donthamsetti P, Newman A, Javitch J, Shi L . What can crystal structures of aminergic receptors tell us about designing subtype-selective ligands?. Pharmacol Rev. 2014; 67(1):198-213. PMC: 4279073. DOI: 10.1124/pr.114.009944. View

11.

Katritch V, Cherezov V, Stevens R . Diversity and modularity of G protein-coupled receptor structures. Trends Pharmacol Sci. 2011; 33(1):17-27. PMC: 3259144. DOI: 10.1016/j.tips.2011.09.003. View

12.

Wang C, Jiang Y, Ma J, Wu H, Wacker D, Katritch V . Structural basis for molecular recognition at serotonin receptors. Science. 2013; 340(6132):610-4. PMC: 3644373. DOI: 10.1126/science.1232807. View

13.

Negro A, Koverech A, Martelletti P . Serotonin receptor agonists in the acute treatment of migraine: a review on their therapeutic potential. J Pain Res. 2018; 11:515-526. PMC: 5848843. DOI: 10.2147/JPR.S132833. View

14.

Villalon C, Centurion D, Valdivia L, de Vries P, Saxena P . Migraine: pathophysiology, pharmacology, treatment and future trends. Curr Vasc Pharmacol. 2004; 1(1):71-84. DOI: 10.2174/1570161033386826. View

15.

Pin J, Galvez T, Prezeau L . Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol Ther. 2003; 98(3):325-54. DOI: 10.1016/s0163-7258(03)00038-x. View

16.

Miyagi H, Asada H, Suzuki M, Takahashi Y, Yasunaga M, Suno C . The discovery of a new antibody for BRIL-fused GPCR structure determination. Sci Rep. 2020; 10(1):11669. PMC: 7363855. DOI: 10.1038/s41598-020-68355-x. View

17.

Wang Y, Lin W, Wu N, Wang S, Chen M, Lin Z . Structural insight into the serotonin (5-HT) receptor family by molecular docking, molecular dynamics simulation and systems pharmacology analysis. Acta Pharmacol Sin. 2019; 40(9):1138-1156. PMC: 6786385. DOI: 10.1038/s41401-019-0217-9. View

18.

Barnes N, Sharp T . A review of central 5-HT receptors and their function. Neuropharmacology. 1999; 38(8):1083-152. DOI: 10.1016/s0028-3908(99)00010-6. View

19.

Cao D, Yu J, Wang H, Luo Z, Liu X, He L . Structure-based discovery of nonhallucinogenic psychedelic analogs. Science. 2022; 375(6579):403-411. DOI: 10.1126/science.abl8615. View

20.

Cao C, Barros-Alvarez X, Zhang S, Kim K, Damgen M, Panova O . Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD. Neuron. 2022; 110(19):3154-3167.e7. PMC: 9583076. DOI: 10.1016/j.neuron.2022.08.006. View