Clinical implications of recent insights into the structural biology of beta2 adrenoceptors

Analysis of the crystal structure of beta-2 adrenoceptors (β₂ARs) is providing new insights into the functioning of this receptor and perhaps of G-protein coupled receptors (GPCRs) as a whole. This class of receptors represents the target of at least a third of the drugs on the market and plays an essential role in the study of therapetic drug-response. Among GPCRs, the β₂AR is the best understood in terms of function, expression and activation. Regarding the interaction of β₂ARs with a specific ligand, polymorphisms, conformational changes and stereoselectivity are important factors. Agonist affinity for β₂ARs is influenced by the polymorphisms of these receptors, which in some cases appear to affect susceptibility to disorders. Conformational changes that take place upon the approach of a given ligand, as well as the stereoselectivity of this class of receptors can modify the intrinsic activity of β₂ARs (and certainly of other receptors as well). Hence, a deepening understanding of these factors can provide new data on affinity and specifically the key residues involved in recognition of β₂AR agonists. The deepening the understanding of the factors involved in ligand affinity for β₂ARs will assist in the development of β₂AR agonists that are more selective and potent, and that have longer term action. Not only are β₂AR agonists employed as therapeutic agents, but also in diagnosis. Currently, the main clinical application of targeting human β₂ARs is to treat asthma with bronchodilators. However, they are also used to treat other maladies in their acute or chronic forms, including heart conditions, metabolic disorders and muscle wasting. This review shows the scope and the possible future clinical implications of data from structures of β₂ARs.