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Rovšnik U, Zhuang Y, Forsberg BO, Carroni M, Yvonnesdotter L, Howard RJ, Lindahl E
Life Sci. Alliance 4 (8) - [2021-08-00; online 2021-07-01]
Ligand-gated ion channels are critical mediators of electrochemical signal transduction across evolution. Biophysical and pharmacological characterization of these receptor proteins relies on high-quality structures in multiple, subtly distinct functional states. However, structural data in this family remain limited, particularly for resting and intermediate states on the activation pathway. Here, we report cryo-electron microscopy (cryo-EM) structures of the proton-activated Gloeobacter violaceus ligand-gated ion channel (GLIC) under three pH conditions. Decreased pH was associated with improved resolution and side chain rearrangements at the subunit/domain interface, particularly involving functionally important residues in the β1-β2 and M2-M3 loops. Molecular dynamics simulations substantiated flexibility in the closed-channel extracellular domains relative to the transmembrane ones and supported electrostatic remodeling around E35 and E243 in proton-induced gating. Exploration of secondary cryo-EM classes further indicated a low-pH population with an expanded pore. These results allow us to define distinct protonation and activation steps in pH-stimulated conformational cycling in GLIC, including interfacial rearrangements largely conserved in the pentameric channel family.
PubMed 34210687
DOI 10.26508/lsa.202101011
Crossref 10.26508/lsa.202101011
pmc: PMC8326787
pii: 4/8/e202101011
PDB: 4NPQ
PDB: 4HFI
PDB: 6ZGD
PDB: 6ZGJ
PDB: 6ZGK