Decrypting the sequence of structural events during the gating transition of pentameric ligand-gated ion channels...

Despite many experimental and computational studies of the gating transition of pentameric ligand-gated ion channels (pLGICs), the structural basis of how ligand binding couples to channel gating remains unknown. By using a newly developed interpolated elastic network model (iENM), we have attempted to compute a likely transition pathway from the closed- to the open-channel conformation of pLGICs as captured by the crystal structures of two prokaryotic pLGICs. The iENM pathway predicts a sequence of structural events that begins at the ligand-binding loops and is followed by the displacements of two key loops (loop 2 and loop 7) at the interface between the extracellular and transmembrane domain, the tilting/bending of the pore-lining M2 helix, and subsequent movements of M4, M3 and M1 helices in the transmembrane domain. The predicted order of structural events is in broad agreement with the Φ-value analysis of α subunit of nicotinic acetylcholine receptor mutants, which supports a conserved core mechanism for ligand-gated channel opening in pLGICs. Further perturbation analysis has supported the critical role of certain intra-subunit and inter-subunit interactions in dictating the above sequence of events.