Cys-loop receptors are pentameric ligand-gated ion channels (LGICs) that mediate fast neurotransmission in the central and peripheral nervous systems, and are so named due to a conserved disulfide linkage in their amino terminal, extracellular ligand binding domains. This superfamily of integral membrane proteins includes the ionophoretic receptors for acetylcholine, serotonin, gamma-aminobutyric acid, glycine, and several invertebrate receptors. Each of these subfamilies comprises receptor subtypes with unique ligand binding and channel gating properties as determined by their specific subunit composition. While there is great variation in the preferences for ligands and gating kinetics between receptor subtypes, the allosteric activation mechanism that communicates binding of small molecule agonists into channel opening some 80-angstroms distant is believed to be conserved among all Cys-loop receptors. Hence, studies on an individual receptor subtype will be informative in terms of design of subtype-selective therapeutics, while simultaneously having broader implications for mechanisms of receptor function for the entire Cys-loop family. Currently, no atomic-resolution structural information exists for this family of receptors;most structural information is based on a 4-angstrom electron microscopy structure and crystallographic structures of a naturally-occurring soluble extracellular domain. The overall goal of this proposal is to determine the 3D structure of a Cys-loop receptor family member at high resolution. This goal will be accomplished by examining representative members from the known families in heterologous expression systems to determine the best candidates for crystallization;a Cys-loop receptor will then be crystallized and its structure determined. The structural studies will be complemented by functional assays that test new structure-based hypothesis regarding mechanisms of state transitions in the receptor. The results will have broad implications for the family in general and the subtype specifically. The proposed studies will provide insight into the major therapeutic targets for neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, and schizophrenia. The results will also improve our ability to design selective therapeutics for these illnesses, thereby limiting deleterious side effects.
| Althoff, Thorsten; Hibbs, Ryan E; Banerjee, Surajit et al. (2014) X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors. Nature 512:333-7 |
| Hibbs, Ryan E; Gouaux, Eric (2011) Principles of activation and permeation in an anion-selective Cys-loop receptor. Nature 474:54-60 |
