Glycine, the simplest amino-acid, is of great medical relevance as an anti-inflammatory, immunomodulatory, cytoprotective, platelet-stabilizing, and anti-angiogenic agent. Several of these beneficial effect of glycine is invoked through activation of glycine-gated chloride channels, glycine receptor (GlyR). GlyR, along with gamma-aminobutyric acid receptor (GABAAR), are anionic members of the pentameric ligand-gated ion channels (pLGIC) family and are principal mediators of inhibitory neurotransmission in the spinal cord and brain stem. glycine and GlyR are implicated in cardiometabolic syndrome (CMS), partially owing to their role in glucose and lipid metabolism and thereby influencing the overall metabolic and inflammatory status of the organs, including heart. The overall goal of this project is to establish a structural framework for understanding allosteric mechanisms underlying gating and modulation in full-length GlyR and provide mechanistic insights into clinical observations. The innovation of the proposal is in the multidisciplinary approach that combines high-resolution structure determination by cryo-EM in a membrane environment (nanodisc) and functional characterization by electrophysiological methods. All of the proposed studies will be carried out in the full-length GlyR alpha1. The proposal is built upon on my extensive preliminary work wherein I have established methods to stably purify the full-length GlyR and determined the structure of the apo-conformation of the channel in a nanodisc environment to 3.3 nominal resolution. We anticipate that the findings from this study will integrate with the wealth of available structural and functional information on the pLGIC family. An understanding of the conformational changes associated with gating and modulation will provide a stepping stone toward the design of better therapeutics.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|