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Nat Chem Biol
2019 Dec 01;1512:1156-1164. doi: 10.1038/s41589-019-0369-4.
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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
.
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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.
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