Description:

Chemical Biology on the Brain: Understanding the Nicotine Receptor

While structural studies continue to advance, obtaining detailed insights into small molecule binding interactions to complex, integral membrane receptors of the mammalian central nervous system remain a significant challenge. Using unnatural amino acid mutagenesis and heterologous expression in Xenopus oocytes, we have developed ways to address specific questions concerning drug-receptor interactions and other features of the nicotinic acetylcholine receptors (nAChR), a prototype receptor system. We can semi-quantitatively evaluate cation-π interactions, hydrophobic interactions, and hydrogen bonding interactions, both to amino acid side chains and to the protein backbone. This provides a general strategy for understanding drug-receptor interactions with chemical precision.