Atomistic insights into human Cys-loop receptors by solution NMR

• Biological significance and therapeutic potential of Cys-loop receptors
• Challenges and strategies for structure and dynamics determination of Cys-loop receptors
• Structural differences among homologous channels differentiating channel pharmacology
• Drug interaction with Cys-loop receptors revealed by NMR

Cys-loop receptors are pentameric ligand-gated ion channels (pLGICs) mediating fast neurotransmission in the central and peripheral nervous systems. They are important targets for many currently used clinical drugs, such as general anesthetics, and for allosteric modulators with potential therapeutic applications. Here, we provide an overview of advances in the use of solution NMR in structural and dynamic characterization of ion channels, particularly human Cys-loop receptors. We present challenges to overcome and realistic solutions for achieving high-resolution structural information for this family of receptors. We discuss how subtle structural differences among homologous channels define unique channel pharmacological properties and advocate the necessity to determine high-resolution structures for individual receptor subtypes. Finally, we describe drug binding to the TMDs of Cys-loop receptors identified by solution NMR and the associated dynamics changes relevant to channel functions. This article is part of a Special Issue entitled: NMR Spectroscopy for Atomistic Views of Biomembranes and Cell Surfaces. Guest Editors: Lynette Cegelski and David P. Weliky.

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