8dpf

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Cryo-EM structure of the 5HT2C receptor (INI isoform) bound to lorcaserin

Structural highlights

8dpf is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 2.84Å
Ligands:CLR, T4U
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

5HT2C_HUMAN G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,-dimethoxy-4-iodophenyl-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and down-stream signaling cascades and promotes the release of Ca(2+) ions from intracellular stores. Regulates neuronal activity via the activation of short transient receptor potential calcium channels in the brain, and thereby modulates the activation of pro-opiomelacortin neurons and the release of CRH that then regulates the release of corticosterone. Plays a role in the regulation of appetite and eating behavior, responses to anxiogenic stimuli and stress. Plays a role in insulin sensitivity and glucose homeostasis.[1] [2] [3] [4]

Publication Abstract from PubMed

RNA editing is a process by which post-transcriptional changes of mRNA nucleotides alter protein function through modification of the amino acid content. The 5HT(2C) serotonin receptor, which undergoes 32 distinct RNA-editing events leading to 24 protein isoforms, is a notable example of this process. These 5HT(2C) isoforms display differences in constitutive activity, agonist/inverse agonist potencies, and efficacies. To elucidate the molecular mechanisms responsible for these effects of RNA editing, we present four active-state 5HT(2C)-transducer-coupled structures of three representative isoforms (INI, VGV, and VSV) with the selective drug lorcaserin (Belviq) and the classic psychedelic psilocin. We also provide a comprehensive analysis of agonist activation and constitutive activity across all 24 protein isoforms. Collectively, these findings reveal a unique hydrogen-bonding network located on intracellular loop 2 that is subject to RNA editing, which differentially affects GPCR constitutive and agonist signaling activities.

Molecular insights into the regulation of constitutive activity by RNA editing of 5HT(2C) serotonin receptors.,Gumpper RH, Fay JF, Roth BL Cell Rep. 2022 Aug 16;40(7):111211. doi: 10.1016/j.celrep.2022.111211. PMID:35977511[5]

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

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Citations
6 reviews cite this structure
Psychedelics: preclinical insights provide directions for future research.
Gumpper et al. (2024)
5 more
11 other articles
No citations found

See Also

References

  1. ↑ Schaerlinger B, Hickel P, Etienne N, Guesnier L, Maroteaux L. Agonist actions of dihydroergotamine at 5-HT2B and 5-HT2C receptors and their possible relevance to antimigraine efficacy. Br J Pharmacol. 2003 Sep;140(2):277-84. doi: 10.1038/sj.bjp.0705437. Epub 2003, Aug 11. PMID:12970106 doi:http://dx.doi.org/10.1038/sj.bjp.0705437
  2. ↑ Cussac D, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Martel JC, Danty N, Rauly-Lestienne I. Agonist-directed trafficking of signalling at serotonin 5-HT2A, 5-HT2B and 5-HT2C-VSV receptors mediated Gq/11 activation and calcium mobilisation in CHO cells. Eur J Pharmacol. 2008 Oct 10;594(1-3):32-8. doi: 10.1016/j.ejphar.2008.07.040., Epub 2008 Jul 30. PMID:18703043 doi:http://dx.doi.org/10.1016/j.ejphar.2008.07.040
  3. ↑ Knauer CS, Campbell JE, Chio CL, Fitzgerald LW. Pharmacological characterization of mitogen-activated protein kinase activation by recombinant human 5-HT2C, 5-HT2A, and 5-HT2B receptors. Naunyn Schmiedebergs Arch Pharmacol. 2009 May;379(5):461-71. doi:, 10.1007/s00210-008-0378-4. Epub 2008 Dec 5. PMID:19057895 doi:http://dx.doi.org/10.1007/s00210-008-0378-4
  4. ↑ Stam NJ, Vanderheyden P, van Alebeek C, Klomp J, de Boer T, van Delft AM, Olijve W. Genomic organisation and functional expression of the gene encoding the human serotonin 5-HT2C receptor. Eur J Pharmacol. 1994 Nov 15;269(3):339-48. PMID:7895773
  5. ↑ Gumpper RH, Fay JF, Roth BL. Molecular insights into the regulation of constitutive activity by RNA editing of 5HT2C serotonin receptors. Cell Rep. 2022 Aug 16;40(7):111211. doi: 10.1016/j.celrep.2022.111211. PMID:35977511 doi:http://dx.doi.org/10.1016/j.celrep.2022.111211

Contents


PDB ID 8dpf

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