Abstract
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.
Highlights
Pentameric ligand-gated ion channels are a family of membrane proteins that open/close an ion-conducting channel in response to an increase/decrease in the binding affinity for specific ligands [1,2,3,4]
A comparison of the ELIC and Gloebacter violaceus (GLIC) structures offers the possibility of a detailed view to the global and local structural changes associated with the gating transition of Pentameric ligand-gated ion channels (pLGICs) despite their variation in bound ligand (ELIC is gated by an unknown ligand, and GLIC is gated by proton instead of a neurotransmitter)
We will first discuss the results of elastic network model (ENM)-based normal mode analysis (NMA) on the ELIC structure, which will motivate the modeling of the gating transition of pLGICs beyond single-mode description
Summary
Pentameric ligand-gated ion channels (pLGICs) are a family of membrane proteins that open/close an ion-conducting channel in response to an increase/decrease in the binding affinity for specific ligands [1,2,3,4]. The crystal structures of ELIC [12] and GLIC [13,14] may represent the low-affinity, closed-channel and high-affinity, open-channel conformations of the pLGICs, respectively. Despite their moderate sequence similarity (,20% sequence identity), the two proteins are highly similar in both secondary and tertiary structures [13,14]. A comparison of the ELIC and GLIC structures offers the possibility of a detailed view to the global and local structural changes associated with the gating transition of pLGICs despite their variation in bound ligand (ELIC is gated by an unknown ligand, and GLIC is gated by proton instead of a neurotransmitter)
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