Scientists map hidden lipid binding sites in brain cell channels
Researchers combined computer simulations with cryo-electron microscopy to identify 25 lipid molecules binding to ion channels—revealing structural details that were invisible in previous studies. The discovery could accelerate drug development for neurological disorders by showing how lipids influence channel behavior in different cellular states.
Originaltitel: Discovery of lipid binding sites in a ligand-gated ion channel by integrating simulations and cryo-EM
<p>Ligand-gated ion channels transduce electrochemical signals in neurons and other excitable cells. Aside fromcanonical ligands, phospholipids are thought to bind specifically to the transmembrane domain of several ionchannels. However, structural details of such lipid contacts remain elusive, partly due to limited resolution ofthese regions in experimental structures. Here, we discovered multiple lipid interactions in the channel GLICby integrating cryo-electron microscopy and large-scale molecular simulations. We identified 25 bound lipidsin the GLIC closed state, a conformation where none, to our knowledge, were previously known. Three lipidswere associated with each subunit in the inner leaflet, including a buried interaction disrupted in mutantsimulations. In the outer leaflet, two intrasubunit sites were evident in both closed and open states, whilea putative intersubunit site was preferred in open-state simulations. This work offers molecular details ofGLIC-lipid contacts particularly in the ill-characterized closed state, testable hypotheses for state-dependentbinding, and a multidisciplinary strategy for modeling protein-lipid interactions.</p>