Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop superfamily are receptors for neurotransmitters such as glycine, glutamate, nicotinic acetylcholine, and serotonin. These receptors are the targets for a number of currently used clinical drugs, including general anesthetics, anti-epileptics (anto-convulsants), sedatives, anxiolytics, and muscle relaxants. Understanding how each of these receptors function and identifying/characterizing the different structural elements that mediate each aspect of their function is imperative for developing new and better drugs as well as improving current treatments. The intracellular domain (ICD) of eukaryotic Cys-loop receptors is the most diverse domain in regards to both the length and amino-acid composition. Because of this diversity, the ICDs are attractive targets for the development of subtype-selective drugs with the promise of fewer side effects than current drugs that target other highly conserved domains.
This technology is a large scale protein expression and purification strategy to mass-produce the ICDs of different pLGICs. It permits the a) optimization and identification conditions for structural determination of the ICDs of superfamily members, and b) identification of proteins and compounds that interact with this domain to identify potential drug targets and lead compounds. Generated data has shown that the ICD pentamerizes, suggesting that it plays a large role in overall receptor structure, and studies have also shown that the ICD directly interacts with cytoplasmic proteins, adding to the probability that the ICD is a promising candidate for pharmaceutical targeting.
Reference number: D-1275
Features, Benefits, & Advantages:
Large protein amounts for drug screening
Enables HTS for new and more specific pharmaceuticals
Elucidation of ICD structures of different pLGIC
Intellectual Property: A US provisional patent, serial number 62410749, was filed on 10/20/16.
Development Stage: The inventor has an established system with four different ICDs, i.e. four different chimeras have been produced. HT crystallization is in progress, and an HT molecule screening (96-well) is in the setup phase.
Michaela Jansen, Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, Texas
Petar Grozdanov, Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, Texas
Keywords: Pentameric ligand-gated ion channels, maltose binding protein, chimeric protein