title: The prokaryote ligand-gated ion channel ELIC captured in a pore blocker-bound conformation by the Alzheimer's disease drug memantine.
abstract: Pentameric ligand-gated ion channels (pLGIC) catalyze the selective transfer of ions across the cell membrane in response to a specific neurotransmitter. A variety of chemically diverse molecules, including the Alzheimer's drug memantine, block ion conduction at vertebrate pLGICs by plugging the channel pore. We show that memantine has similar potency in ELIC, a prokaryotic pLGIC, when it contains an F16'S pore mutation. X-ray crystal structures, using both memantine and its derivative, Br-memantine, reveal that the ligand is localized at the extracellular entryway of the channel pore, and the pore is in a more closed conformation than wild-type ELIC in both the presence and absence of memantine. However, using voltage clamp fluorometry we observe fluorescence changes in opposite directions during channel activation and pore block, revealing an additional conformational transition not apparent from the crystal structures. These results have important implications for drugs such as memantine, which block channel pores.
authors.affiliation: Laboratory of Structural Neurobiology, KU Leuven, Leuven 3000, Belgium. Electronic address: chris.ulens@med.kuleuven.be.
authors.forename: Chris
authors.initials: C
authors.lastname: Ulens
authors.affiliation: Laboratory of Structural Neurobiology, KU Leuven, Leuven 3000, Belgium.
authors.forename: Radovan
authors.initials: R
authors.lastname: Spurny
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Thompson
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
authors.forename: Mona
authors.initials: M
authors.lastname: Alqazzaz
authors.affiliation: Laboratory of Structural Neurobiology, KU Leuven, Leuven 3000, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Debaveye
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Lu
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
authors.forename: Kerry
authors.initials: K
authors.lastname: Price
authors.affiliation: VillaPharma Research, Murcia 30320, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Villalgordo
authors.affiliation: Molecular Sciences, Janssen R&D, Beerse 2340, Belgium.
authors.forename: Gary
authors.initials: G
authors.lastname: Tresadern
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lynch
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
authors.forename: Sarah C R
authors.initials: SC
authors.lastname: Lummis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry; D018360:Crystallography, X-Ray; D016974:Dickeya chrysanthemi / Q000737:chemistry; D006801:Humans; D058446:Ligand-Gated Ion Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008559:Memantine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009154:Mutation; D009865:Oocytes / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques; D010649:Phenylalanine / Q000737:chemistry; D011487:Protein Conformation; D012299:Rimantadine / Q000494:pharmacology; D014981:Xenopus
chemical_list: D001426:Bacterial Proteins; D058446:Ligand-Gated Ion Channels; D012299:Rimantadine; D010649:Phenylalanine; D008559:Memantine