TY - JOUR
T1 - X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors
AU - Althoff, Thorsten
AU - Hibbs, Ryan E.
AU - Banerjee, Surajit
AU - Gouaux, Eric
N1 - Funding Information:
Acknowledgements We thank all staff of beamline 24-ID-C at the Advanced Photon Source. We thank L. Vaskalis and H. Owen for help in figure and manuscript preparation, respectively. D. Cawley at the Vaccine and Gene Therapy Institute, OHSU, provided the monoclonal antibody. We appreciate discussions with Gouaux laboratory members. This work was supported by a postdoctoral fellowship (Forschungsstipendium AL 1725-1/1) from the Deutsche Forschungsgemeinschaft to T.A. and an individual NIH National Research Service Award (F32NS061404) to R.E.H; E.G. is supported by the NIH and is an investigator with the Howard Hughes Medical Institute.
PY - 2014/8/21
Y1 - 2014/8/21
N2 - Cys-loop receptors are neurotransmitter-gated ion channels that are essential mediators of fast chemical neurotransmission and are associated with a large number of neurological diseases and disorders, as well as parasitic infections1-4. Members of this ion channel superfamily mediate excitatory or inhibitory neurotransmission depending on their ligand and ion selectivity. Structural information for Cys-loop receptors comes from several sources including electron microscopic studies of the nicotinic acetylcholine receptor5, high-resolution X-ray structures of extracellular domains6 and X-ray structures of bacterial orthologues 7-10. In 2011 our group published structures of the Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in complex with the allosteric partial agonist ivermectin, which provided insights into the structure of a possibly open state of a eukaryotic Cys-loop receptor, the basis for anion selectivity and channel block, and the mechanism by which ivermectin and related molecules stabilize the open state and potentiate neurotransmitter binding 11. However, there remain unanswered questions about the mechanism of channel opening and closing, the location and nature of the shut ion channel gate, the transitions between the closed/resting, open/activated and closed/desensitized states, and the mechanism by which conformational changes are coupled between the extracellular, orthosteric agonist binding domain and the transmembrane, ion channel domain. Here we present two conformationally distinct structures of C. elegans GluCl in the absence of ivermectin. Structural comparisons reveal a quaternary activation mechanism arising from rigid-body movements between the extracellular and transmembrane domains and a mechanism for modulation of the receptor by phospholipids.
AB - Cys-loop receptors are neurotransmitter-gated ion channels that are essential mediators of fast chemical neurotransmission and are associated with a large number of neurological diseases and disorders, as well as parasitic infections1-4. Members of this ion channel superfamily mediate excitatory or inhibitory neurotransmission depending on their ligand and ion selectivity. Structural information for Cys-loop receptors comes from several sources including electron microscopic studies of the nicotinic acetylcholine receptor5, high-resolution X-ray structures of extracellular domains6 and X-ray structures of bacterial orthologues 7-10. In 2011 our group published structures of the Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in complex with the allosteric partial agonist ivermectin, which provided insights into the structure of a possibly open state of a eukaryotic Cys-loop receptor, the basis for anion selectivity and channel block, and the mechanism by which ivermectin and related molecules stabilize the open state and potentiate neurotransmitter binding 11. However, there remain unanswered questions about the mechanism of channel opening and closing, the location and nature of the shut ion channel gate, the transitions between the closed/resting, open/activated and closed/desensitized states, and the mechanism by which conformational changes are coupled between the extracellular, orthosteric agonist binding domain and the transmembrane, ion channel domain. Here we present two conformationally distinct structures of C. elegans GluCl in the absence of ivermectin. Structural comparisons reveal a quaternary activation mechanism arising from rigid-body movements between the extracellular and transmembrane domains and a mechanism for modulation of the receptor by phospholipids.
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U2 - 10.1038/nature13669
DO - 10.1038/nature13669
M3 - Article
C2 - 25143115
AN - SCOPUS:84906568725
SN - 0028-0836
VL - 512
SP - 333
EP - 337
JO - Nature
JF - Nature
IS - 7514
ER -