Crystal structure of the α<sub>1B</sub>-adrenergic receptor reveals molecular determinants of selective ligand recognition.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35046410.
- Also identified by DOI 10.1038/s41467-021-27911-3 and PMC identifier 8770593.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
α-adrenergic receptors (αARs) are G protein-coupled receptors that regulate vital functions of the cardiovascular and nervous systems. The therapeutic potential of αARs, however, is largely unexploited and hampered by the scarcity of subtype-selective ligands. Moreover, several aminergic drugs either show off-target binding to αARs or fail to interact with the desired subtype. Here, we report the crystal structure of human α<sub>1B</sub>AR bound to the inverse agonist (+)-cyclazosin, enabled by the fusion to a DARPin crystallization chaperone. The α<sub>1B</sub>AR structure allows the identification of two unique secondary binding pockets. By structural comparison of α<sub>1B</sub>AR with α<sub>2</sub>ARs, and by constructing α<sub>1B</sub>AR-α<sub>2C</sub>AR chimeras, we identify residues 3.29 and 6.55 as key determinants of ligand selectivity. Our findings provide a basis for discovery of α<sub>1B</sub>AR-selective ligands and may guide the optimization of aminergic drugs to prevent off-target binding to αARs, or to elicit a selective interaction with the desired subtype.
Medical subject headings
- Crystallography, X-Ray
- Receptors, Adrenergic, alpha-1