[
    {
        "id": "authors:3s49q-xjj09",
        "collection": "authors",
        "collection_id": "3s49q-xjj09",
        "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160414-084908996",
        "type": "conference_item",
        "title": "Probing binding interactions of agonists at a nicotinic acetylcholine receptor subtype important to addiction and Parkinson's disease",
        "author": [
            {
                "family_name": "Post",
                "given_name": "Michael R.",
                "orcid": "0000-0002-3214-7619",
                "clpid": "Post-M-R"
            },
            {
                "family_name": "Lester",
                "given_name": "Henry",
                "orcid": "0000-0002-5470-5255",
                "clpid": "Lester-H-A"
            },
            {
                "family_name": "Dougherty",
                "given_name": "Dennis A.",
                "orcid": "0000-0003-1464-2461",
                "clpid": "Dougherty-D-A"
            }
        ],
        "abstract": "Nicotine addiction is still a major problem in American society. Sixteen percent of adults report smoking regularly, resulting in\n96 billion dollars in healthcare costs per yr. Parkinson's disease is incurable, with 6,000 new diagnoses each year - it is the 14th\nleading cause of death in the US. Parkinson's disease and nicotine addiction are disorders of the dopamine pathway, making\n\u03b16\u03b22- contg. subtypes of the nicotinic acetylcholine receptor (nAChR) , which are ligand gated ion channels localized to\ndopaminergic neurons, an attractive target. Advanced knowledge of the binding site, which sits at the interface of \u03b16 and \u03b22,\ncould lead to design of agonists which specifically target that subtype. When \u03b16L9'S\u03b22_(LFM/AAQA)L9'S (\u03b16\u03b22 ) mRNA is injected in\nX. Laevis oocytes, heterologous expression and activation of a pure and stoichiometrically controlled population of receptors is\nobsd. Currents are high enough in the \u03b16\u03b22 system to tolerate nonsense suppression- based non- canonical amino acid\nmutagenesis, which allows for structure-function studies between the receptor and agonists. Initial structure-function studies\nprobed for a cation- \u03c0 interaction between TrpB and several agonists. This was accomplished using a series of substituted\ntryptophans. Electron- withdrawing groups such as fluorine were incrementally added to the indole side chain, and effects on\nbinding were compared to ab initio calcd. expected binding energies. Results show that acetylcholine makes a cation- \u03c0\ninteraction, while nicotine and TC- 299423 do not. They do however make a hydrogen bond to TrpB's backbone carbonyl. The\namide backbone was mutated to an ester bond via an alpha- hydroxy acid substitution at the amino acid adjacent to TrpB\nmaking the carbonyl a weaker hydrogen bond acceptor, and a corresponding loss in function was obsd. The hydrogen bond to\nnicotine was then quantified with a double- mutant cycle anal. utilizing N'- methylnicotinium and the amide-ester mutation. It\nshowed the interaction to have a coupling energy of \u223c2 kcal/mol. Further studies of this important pharmacophore are\nunderway.",
        "publisher": "Caltech Library",
        "publication_date": "2016-03"
    }
]