{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["13(1)"],"submitter":["Deluigi M"],"pubmed_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."],"journal":["Nature communications"],"pagination":["382"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8770593"],"repository":["biostudies-literature"],"pubmed_title":["Crystal structure of the α<sub>1B</sub>-adrenergic receptor reveals molecular determinants of selective ligand recognition."],"pmcid":["PMC8770593"],"pubmed_authors":["Vaid TM","Cridge RR","Mittl PRE","Pluckthun A","Klenk C","Zerbe O","Chalmers DK","Eberle SA","Deluigi M","Scott DJ","Morstein L","Schuster M","Klipp A","Merklinger L","Vacca S","de Zhang LA","Egloff P"],"additional_accession":[]},"is_claimable":false,"name":"Crystal structure of the α<sub>1B</sub>-adrenergic receptor reveals molecular determinants of selective ligand recognition.","description":"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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Jan","modification":"2026-05-31T19:58:04.917Z","creation":"2025-04-19T22:40:13.057Z"},"accession":"S-EPMC8770593","cross_references":{"pubmed":["35046410"],"doi":["10.1038/s41467-021-27911-3"]}}