Identification of open conformation of a pLGIC stabilized by outer leaflet phospholipid

Phospholipids are the principal lipid component of plasma membranes and modulate the function of integral membrane proteins including pentameric ligand-gated ion channels (pLGIC). For example, anionic phospholipids are positive modulators of pLGIC function. Though this modulatory effect has been studied for several decades the structural mechanism has remained largely elusive. Using cryoEM and stopped-flow measurements of ion channel function in asymmetric proteoliposomes, we determine the anionic phospholipid 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG) positively modulates the pLGIC, ELIC, by binding to an outer leaflet site in the M4-M3-M1 grove.