The Binding Site of Aminergic G Protein–Coupled Receptors: The Transmembrane Segments and Second Extracellular Loop

In the current chapter, we review approaches to the identification of the residues forming the binding sites for agonists, antagonists, and allosteric modulators in the family of aminergic G protein–coupled receptors (GPCRs). We then review the structural bases for ligand binding and pharmacological specificity based on the application of these methods to muscarinic cholinergic, adrenergic, dopaminergic, serotonergic, and histaminergic receptors, using the high resolution rhodopsin structure as a template. Furthermore, we propose a critical role of the second extracellular loop in forming the binding site for small molecular weight aminergic ligands, much as this loop dives down into the binding-site crevice and contacts retinal in rhodopsin.