Probing G protein-coupled receptor-ligand interactions with targeted photoactivatable cross-linkers

It has been 50 years since F. H. Westheimer and colleagues reported the first use of a photoactivatable cross-linking reagent to study the active site of chymotrypsin. In studies of seven transmembrane helical receptors, also known as G protein-coupled receptors (GPCRs), recent simultaneous advances in structural biology, molecular dynamics simulations, and amber codon suppression methods have allowed the development of a targeted photo-cross-linking strategy to probe receptor-ligand interactions in cell membranes. We review here recent advances in targeted photo-cross-linking of GPCR-ligand complexes in the context of extensive earlier work that primarily relied upon the use of ligand analogues with photoactivatable constituents.