Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 19, Issue 6, Pages 642-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2307
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Funding
- European 'NeuroCypres'
- Louis D. Foundation from the Institut de Francee
- Grand Equipement National de Calcul Intensif (GENCI)-Institut du Developpement et des Ressources en Informatique Scientifique (IDRIS) [2010-072292]
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Pentameric ligand-gated ion channels mediate signal transduction through conformational transitions between closed-pore and open-pore states. To stabilize a closed conformation of GLIC, a bacterial proton-gated homolog from Gloeobacter violaceus whose open structure is known, we separately generated either four cross-links or two single mutations. We found all six mutants to be in the same 'locally closed' conformation using X-ray crystallography, sharing most of the features of the open form but showing a locally closed pore as a result of a concerted bending of all of its M2 helices. The mutants adopt several variant conformations of the M2-M3 loop, and in all cases an interacting lipid that is observed in the open form disappears. A single cross-linked mutant is functional, according to electrophysiology, and the locally closed structure of this mutant indicates that it has an increased flexibility. Further cross-linking, accessibility and molecular dynamics data suggest that the locally closed form is a functionally relevant conformation that occurs during allosteric gating transitions.
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