title: Open-channel structures of the human glycine receptor α1 full-length transmembrane domain.
abstract: Glycine receptors play a major role in mediating fast inhibitory neurotransmission in the spinal cord and brain stem, yet their high-resolution structures remain unsolved. We determined open-channel structures of the full-length transmembrane domain (TMD) of the human glycine receptor α1-subunit (hGlyR-α1) using nuclear magnetic resonance (NMR) spectroscopy and electron micrographs. hGlyR-α1 TMD spontaneously forms pentameric Cl(-)-conducting channels, with structures sharing overall topology observed in crystal structures of homologous bacterial and nematode pentameric ligand-gated ion channels (pLGICs). However, the mammalian hGlyR-α1 structures present several distinctive features, including a shorter, pore-lining TM2 helix with helical unwinding near the C-terminal end, a TM3 helical kink at A288 that partially overlaps with the homologous ivermectin-binding site in GluCl, and a highly dynamic segment between S267(15') of TM2 and A288 that likely affects allosteric modulations of channel function. Our structures provide additional templates for identifying potential drug targets in GlyRs and other mammalian pLGICs.
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Mowrey
authors.forename: Tanxing
authors.initials: T
authors.lastname: Cui
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Jia
authors.forename: Dejian
authors.initials: D
authors.lastname: Ma
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Makhov
authors.forename: Peijun
authors.initials: P
authors.lastname: Zhang
authors.forename: Pei
authors.initials: P
authors.lastname: Tang
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
mesh_terms: D002712:Chlorides / Q000737:chemistry; D020285:Cryoelectron Microscopy; D006801:Humans; D015640:Ion Channel Gating; D008564:Membrane Potentials; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010539:Permeability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018009:Receptors, Glycine / Q000819:agonists / Q000737:chemistry* / Q000648:ultrastructure; D053835:Unilamellar Liposomes / Q000737:chemistry
chemical_list: D002712:Chlorides; D018009:Receptors, Glycine; D053835:Unilamellar Liposomes