Structural insights into the lipid and ligand regulation of serotonin receptors

Structure of serotonin receptors: molecular underpinning of receptor activation and modulation

“…The five 5-HT 1 receptor structures determined by Xu and colleagues 1 display the canonical seven-TM fold of G-protein-coupled receptors (GPCRs) and are similar to a previously described 5-HT 1B –G-protein complex. 2 For the structures in the active state, the cytoplasmic pocket of the 5-HT receptors is open for G-protein binding.…”

“…Although multiple studies demonstrated a vital role of cholesterol in the function and organization of GPCRs, the underlying molecular mechanisms remained largely enigmatic. The structure of 5-HT 1A determined by Xu et al 1 explains the importance of cholesterol for GPCR activity. Two cholesterol molecules make direct contact with the PtdIns4P molecule at the receptor–G-protein interface.…”

“…The structural basis of the regulation of serotonin (5-hydroxytryptamine, 5-HT) receptors by ligands and lipids is only emerging. A recent study by Xu and colleagues 1 published in Nature addresses this issue by resolving five structures of 5-HT 1 receptor–G protein complexes. These include 5-HT 1A in the apo-state, i.e.…”

“…ECL1, extracellular loop 1. Reprinted by permission from Springer Nature: Nature, Xu et al © (2021), 1 under exclusive licence to Springer Nature Limited . …”

“…However, the development of highly selective drug candidates requires a detailed understanding of the molecular underpinnings that determine receptor activation and signaling. Xu and colleagues 1 provide key insights into these molecular determinants. Across twelve 5-HT GPCRs, which all bind serotonin, only eight out of 22 amino acids are identical in the ligand-binding pocket.…”