1. Pasteur Institute, G5 Group of Channel-Receptor, CNRS URA 2182
2. Pasteur Institute, Unit of Structural Dynamics of Macromolecules, CNRS URA 2185
3. Pasteur Institute, CNRS URA 2182, F75015, Paris, France
4. Institut de Biologie Physico-Chimique, CNRS UPR 9080, 75005 Paris, France
5. These authors contributed equally to this work.

Correspondence to: Marc Delarue²Pierre-Jean Corringer¹ Correspondence and requests for materials should be addressed to M.D. (Email: marc.delarue@pasteur.fr) or P.-J.C. (Email: pjcorrin@pasteur.fr).

Abstract

Pentameric ligand-gated ion channels from the Cys-loop family mediate fast chemo-electrical transduction^{1, 2, 3}, but the mechanisms of ion permeation and gating of these membrane proteins remain elusive. Here we present the X-ray structure at 2.9 Å resolution of the bacterial Gloeobacter violaceus pentameric ligand-gated ion channel homologue⁴ (GLIC) at pH 4.6 in an apparently open conformation. This cationic channel is known to be permanently activated by protons⁵. The structure is arranged as a funnel-shaped transmembrane pore widely open on the outer side and lined by hydrophobic residues. On the inner side, a 5 Å constriction matches with rings of hydrophilic residues that are likely to contribute to the ionic selectivity^{6, 7, 8, 9}. Structural comparison with ELIC, a bacterial homologue from Erwinia chrysanthemi solved in a presumed closed conformation¹⁰, shows a wider pore where the narrow hydrophobic constriction found in ELIC is removed. Comparative analysis of GLIC and ELIC reveals, in concert, a rotation of each extracellular -sandwich domain as a rigid body, interface rearrangements, and a reorganization of the transmembrane domain, involving a tilt of the M2 and M3 -helices away from the pore axis. These data are consistent with a model of pore opening based on both quaternary twist and tertiary deformation.

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