Structural basis for the β-adrenergic receptor subtype selectivity of the representative agonists and antagonists.

The β(3)-adrenegic receptor (β(3)-AR) selectivity over β(1)- and β(2)-ARs has been the most important aspect for successful therapeutic agents for obesity and type-II diabetes, as the concomitant activation of β(1)- and β(2)-ARs would lead to undesirable side effects, such as increased heart rate. In order to explore the structural basis for the β-AR subtype selectivity of agonists and anatagonists, a three-dimensional structure of until date unresolved β(3)-AR has been modeled, compared with the resolved X-ray structures of β(1)- and β(2)-ARs, and used to study its stereoselective binding with until-date known diverse classes of representative agonists and antagonist. The obtained binding structures and calculated prime molecular mechanics-generalized Born surface area (MM-GBSA) binding free energies consistently reveal that while the subtype selectivity is strongly governed by the residues present in the extracellular ends of TM3, TM5, TM6, TM7 helices and of the ECL2 domain, the binding affinity is governed by the conserved residues present in the deep pocket limiting the degree of conformational and rotational freedoms to the bound ligand. The study demonstrates that the key structural requirements for the β(3)-selectivity are: (i) a negatively ionizable group (NIG) for direct interaction with β(3)-specific residue R315(6.58), (ii) a linker (9-10 Å length) between the protonated amine and NIG, and (iii) a substituted aryl ring directly attached to the β-hydroxyl carbon. The new computational insights acquired in this study are expected to be valuable in structure-based rational design of high-affinity agonists and antagonists with pronounced β(3)-selectivity for successful therapeutic agents for type-II diabetes and obesity.