8DPI

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

Summary for 8DPI

• Entry DOI: 10.2210/pdb8dpi/pdb
• EMDB information: 27636
• Descriptor: 5-hydroxytryptamine receptor 2C, G-alpha subunit q (Gi2-mini-Gq chimera), Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (7 entities in total)
• Functional Keywords: gpcr, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 156436.31

Authors

Gumpper, R.H.,Fay, J.F.,Roth, B.L. (deposition date: 2022-07-15, release date: 2022-08-24, Last modification date: 2024-10-30)

Primary citation

Gumpper, R.H.,Fay, J.F.,Roth, B.L.
Molecular insights into the regulation of constitutive activity by RNA editing of 5HT 2C serotonin receptors.
Cell Rep, 40:111211-111211, 2022

PubMed Abstract: 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 serotonin receptor, which undergoes 32 distinct RNA-editing events leading to 24 protein isoforms, is a notable example of this process. These 5HT 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-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.

PubMed: 35977511
DOI: 10.1016/j.celrep.2022.111211

Experimental method

ELECTRON MICROSCOPY (3.4 Å)