INTRODUCTION

Many interactions studied in the biological and biomedical sciences occur with receptors at membrane surfaces. Prominent examples are neuroreceptors, cytokine receptors, ligand-gated ion channels, G protein-coupled receptors (GPCRs), and antibody and cytokine receptors. Interactions with these receptors are especially important to academics and the pharmaceutical industry as almost half of the 100 best-selling drugs on the market are targeted to a membrane receptor. To better understand the binding mechanisms of ligands with these receptors, the ligand-receptor interactions must be probed directly in vivo or in reconstituted membrane systems. Most techniques for detailed kinetic analysis of molecular recognition events are applied in solution phase using a truncated, soluble form of the receptor. Membrane receptors, however, possess significant hydrophobic domains and are likely to have different tertiary structures and binding affinities in solution relative to those occurring in a membrane environment. This approach is limited to receptors containing a single transmembrane domain and does not allow the study of signaling cascades triggered by ligand binding to a receptor or the investigation of complex membrane proteins that often homo- or heterodimerize. However, in the last 10 years there has been significant progress in the development of techniques that allow the analysis of membrane-associated ligand–receptor interactions in a model resembling their native membrane environment.

Biophysical techniques such as patch clamping, magic angle spinning nuclear magnetic resonance (MAS-NMR), fluorescence correlation spectroscopy, fluorescence resonance energy transfer, and analytical ultracentrifugation have been applied to the analysis of binding to whole cells, membrane protoplasts, and proteoliposomes.