Nuclear magnetic resonance (NMR) spectroscopy allows the determination of atomic-level information on intermolecular interactions, molecular structure, and molecular dynamics in the cellular environment. This may be broadly divided into studies focused on obtaining detailed molecular information in the intracellular context ("in-cell") or those focused on characterizing molecules or events at the cell surface ("on-cell"). In this review, we outline some key NMR techniques applied for on-cell NMR studies through both solution- and solid-state NMR and survey studies that have used these techniques to uncover key information. In particular, we focus on the application of on-cell NMR spectroscopy to characterize ligand interactions with cell surface membrane proteins such as G-protein coupled receptors (GPCRs) and receptor tyrosine kinases. These techniques allow for quantification of binding affinities, competitive binding assays, delineation of ligands involved in binding, ligand bound-state conformational determination, evaluation of receptor structuring and dynamics, and inference of distance constraints characteristic of the ligand-receptor bound state. Interestingly, it is possible to avoid the barriers of production and purification of membrane proteins while obtaining directly physiologically relevant information through on-cell NMR. We also provide a brief survey of the applicability of on-cell NMR approaches to other classes of cell surface molecules.
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