Crystal structure of the α1B-adrenergic receptor reveals molecular determinants of selective ligand recognition

This study reports the X-ray structure of the alpha(1B)-adrenergic G protein-coupled receptor bound to an inverse agonist, and unveils key determinants of subtype-selective ligand binding that may help the design of aminergic drugs with fewer side-effects. alpha-adrenergic receptors (alpha ARs) are G protein-coupled receptors that regulate vital functions of the cardiovascular and nervous systems. The therapeutic potential of alpha ARs, however, is largely unexploited and hampered by the scarcity of subtype-selective ligands. Moreover, several aminergic drugs either show off-target binding to alpha ARs or fail to interact with the desired subtype. Here, we report the crystal structure of human alpha(1B)AR bound to the inverse agonist (+)-cyclazosin, enabled by the fusion to a DARPin crystallization chaperone. The alpha(1B)AR structure allows the identification of two unique secondary binding pockets. By structural comparison of alpha(1B)AR with alpha(2)ARs, and by constructing alpha(1B)AR-alpha(2C)AR chimeras, we identify residues 3.29 and 6.55 as key determinants of ligand selectivity. Our findings provide a basis for discovery of alpha(1B)AR-selective ligands and may guide the optimization of aminergic drugs to prevent off-target binding to alpha ARs, or to elicit a selective interaction with the desired subtype.

Automated summary

This study reports the X-ray structure of the alpha(1B)-adrenergic G protein-coupled receptor bound to an inverse agonist and identifies key determinants of subtype-selective ligand binding. This finding is important for the design of aminergic drugs with fewer side-effects.