7xtb

Serotonin 6 (5-HT6) receptor-Gs-Nb35 complexSerotonin 6 (5-HT6) receptor-Gs-Nb35 complex

Structural highlights

7xtb is a 5 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.3Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

C562_ECOLX Electron-transport protein of unknown function.5HT6R_HUMAN G-protein coupled receptor for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone and a mitogen (PubMed:35714614, PubMed:36989299, PubMed:37327704, PubMed:8522988). Also has a high affinity for tricyclic psychotropic drugs (By similarity). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors (PubMed:35714614). HTR6 is coupled to G(s) G alpha proteins and mediates activation of adenylate cyclase activity (PubMed:35714614, PubMed:37327704). Controls pyramidal neurons migration during corticogenesis, through the regulation of CDK5 activity (By similarity). Is an activator of mTOR signaling (PubMed:23027611).[UniProtKB:P31388][UniProtKB:Q9R1C8]^[1] ^[2] ^[3] ^[4] ^[5]

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^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Meffre J, Chaumont-Dubel S, Mannoury la Cour C, Loiseau F, Watson DJ, Dekeyne A, Séveno M, Rivet JM, Gaven F, Déléris P, Hervé D, Fone KC, Bockaert J, Millan MJ, Marin P. 5-HT(6) receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia. EMBO Mol Med. 2012 Oct;4(10):1043-56. PMID:23027611 doi:10.1002/emmm.201201410
↑ 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
↑ He L, Zhao Q, Qi J, Wang Y, Han W, Chen Z, Cong Y, Wang S. Structural insights into constitutive activity of 5-HT(6) receptor. Proc Natl Acad Sci U S A. 2023 Apr 4;120(14):e2209917120. PMID:36989299 doi:10.1073/pnas.2209917120
↑ Pei Y, Wen X, Guo SC, Yang ZS, Zhang R, Xiao P, Sun JP. Structural insight into the selective agonist ST1936 binding of serotonin receptor 5-HT6. Biochem Biophys Res Commun. 2023 Jun 5;671:327-334. PMID:37327704 doi:10.1016/j.bbrc.2023.05.126
↑ Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW. Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor. J Neurochem. 1996 Jan;66(1):47-56. PMID:8522988 doi:10.1046/j.1471-4159.1996.66010047.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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OCA

[1] Meffre J, Chaumont-Dubel S, Mannoury la Cour C, Loiseau F, Watson DJ, Dekeyne A, Séveno M, Rivet JM, Gaven F, Déléris P, Hervé D, Fone KC, Bockaert J, Millan MJ, Marin P. 5-HT(6) receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia. EMBO Mol Med. 2012 Oct;4(10):1043-56. PMID:23027611 doi:10.1002/emmm.201201410

[2] 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

[3] He L, Zhao Q, Qi J, Wang Y, Han W, Chen Z, Cong Y, Wang S. Structural insights into constitutive activity of 5-HT(6) receptor. Proc Natl Acad Sci U S A. 2023 Apr 4;120(14):e2209917120. PMID:36989299 doi:10.1073/pnas.2209917120

[4] Pei Y, Wen X, Guo SC, Yang ZS, Zhang R, Xiao P, Sun JP. Structural insight into the selective agonist ST1936 binding of serotonin receptor 5-HT6. Biochem Biophys Res Commun. 2023 Jun 5;671:327-334. PMID:37327704 doi:10.1016/j.bbrc.2023.05.126

[5] Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW. Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor. J Neurochem. 1996 Jan;66(1):47-56. PMID:8522988 doi:10.1046/j.1471-4159.1996.66010047.x

[6] 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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