7xta

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^[3]

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