| Structural highlights
Function
C562_ECOLX Electron-transport protein of unknown function.5HT4R_HUMAN G-protein coupled receptor for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone and a mitogen (PubMed:10821780, PubMed:16102731, PubMed:35714614, PubMed:9603189). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors (PubMed:16102731, PubMed:35714614). HTR4 is coupled to G(s) G alpha proteins and mediates activation of adenylate cyclase activity (PubMed:16102731, PubMed:35714614).[1] [2] [3] [4]
Publication Abstract from PubMed
Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of G(s), G(i,) or G(q) proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT(4), 5-HT(6), and 5-HT(7) with G(s), and 5-HT(4) with G(i1). The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for G(s) and G(i), respectively. We find that the macro-switch by the TM5-TM6 length is shared by class A GPCR-G protein structures. Furthermore, we discover specific residues within TM5 and TM6 that function as micro-switches to form specific interactions with G(s) or G(i). Together, these results present a common mechanism of G(s) versus G(i) protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors.
GPCRs steer G(i) and G(s) selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors.,Huang S, Xu P, Shen DD, Simon IA, Mao C, Tan Y, Zhang H, Harpsoe K, Li H, Zhang Y, You C, Yu X, Jiang Y, Zhang Y, Gloriam DE, Xu HE Mol Cell. 2022 Jul 21;82(14):2681-2695.e6. doi: 10.1016/j.molcel.2022.05.031. , Epub 2022 Jun 16. PMID:35714614[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mialet J, Dahmoune Y, Lezoualc'h F, Berque-Bestel I, Eftekhari P, Hoebeke J, Sicsic S, Langlois M, Fischmeister R. Exploration of the ligand binding site of the human 5-HT(4) receptor by site-directed mutagenesis and molecular modeling. Br J Pharmacol. 2000 Jun;130(3):527-38. PMID:10821780 doi:10.1038/sj.bjp.0703356
- ↑ Kamel R, Eftekhari P, Garcia S, Berthouze M, Berque-Bestel I, Peter JC, Lezoualc'h F, Hoebeke J. A high-affinity monoclonal antibody with functional activity against the 5-hydroxytryptaminergic (5-HT4) receptor. Biochem Pharmacol. 2005 Oct 1;70(7):1009-18. PMID:16102731 doi:10.1016/j.bcp.2005.07.005
- ↑ Huang S, Xu P, Shen DD, Simon IA, Mao C, Tan Y, Zhang H, Harpsoe K, Li H, Zhang Y, You C, Yu X, Jiang Y, Zhang Y, Gloriam DE, Xu HE. GPCRs steer Gi and Gs selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors. Mol Cell. 2022 Jul 21;82(14):2681-2695.e6. doi: 10.1016/j.molcel.2022.05.031., Epub 2022 Jun 16. PMID:35714614 doi:http://dx.doi.org/10.1016/j.molcel.2022.05.031
- ↑ Blondel O, Gastineau M, Dahmoune Y, Langlois M, Fischmeister R. Cloning, expression, and pharmacology of four human 5-hydroxytryptamine 4 receptor isoforms produced by alternative splicing in the carboxyl terminus. J Neurochem. 1998 Jun;70(6):2252-61. PMID:9603189 doi:10.1046/j.1471-4159.1998.70062252.x
- ↑ Huang S, Xu P, Shen DD, Simon IA, Mao C, Tan Y, Zhang H, Harpsoe K, Li H, Zhang Y, You C, Yu X, Jiang Y, Zhang Y, Gloriam DE, Xu HE. GPCRs steer Gi and Gs selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors. Mol Cell. 2022 Jul 21;82(14):2681-2695.e6. doi: 10.1016/j.molcel.2022.05.031., Epub 2022 Jun 16. PMID:35714614 doi:http://dx.doi.org/10.1016/j.molcel.2022.05.031
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