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Nat Chem Biol January 1, 2019; 15 (12): 1156-1164.
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A lipid site shapes the agonist response of a pentameric ligand-gated ion channel.

Hénault CM , Govaerts C , Spurny R , Brams M , Estrada-Mondragon A , Lynch J , Bertrand D , Pardon E , Evans GL , Woods K , Elberson BW , Cuello LG , Brannigan G , Nury H , Steyaert J , Baenziger JE , Ulens C .

Phospholipids are key components of cellular membranes and are emerging as important functional regulators of different membrane proteins, including pentameric ligand-gated ion channels (pLGICs). Here, we take advantage of the prokaryote channel ELIC (Erwinia ligand-gated ion channel) as a model to understand the determinants of phospholipid interactions in this family of receptors. A high-resolution structure of ELIC in a lipid-bound state reveals a phospholipid site at the lower half of pore-forming transmembrane helices M1 and M4 and at a nearby site for neurosteroids, cholesterol or general anesthetics. This site is shaped by an M4-helix kink and a Trp-Arg-Pro triad that is highly conserved in eukaryote GABAA/C and glycine receptors. A combined approach reveals that M4 is intrinsically flexible and that M4 deletions or disruptions of the lipid-binding site accelerate desensitization in ELIC, suggesting that lipid interactions shape the agonist response. Our data offer a structural context for understanding lipid modulation in pLGICs.

PubMed ID: 31591563
PMC ID: PMC8423587
Article link: Nat Chem Biol
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