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Publication Abstract from PubMed

alpha-adrenergic receptors (alphaARs) are G protein-coupled receptors that regulate vital functions of the cardiovascular and nervous systems. The therapeutic potential of alphaARs, however, is largely unexploited and hampered by the scarcity of subtype-selective ligands. Moreover, several aminergic drugs either show off-target binding to alphaARs or fail to interact with the desired subtype. Here, we report the crystal structure of human alpha1BAR bound to the inverse agonist (+)-cyclazosin, enabled by the fusion to a DARPin crystallization chaperone. The alpha1BAR structure allows the identification of two unique secondary binding pockets. By structural comparison of alpha1BAR with alpha2ARs, and by constructing alpha1BAR-alpha2CAR chimeras, we identify residues 3.29 and 6.55 as key determinants of ligand selectivity. Our findings provide a basis for discovery of alpha1BAR-selective ligands and may guide the optimization of aminergic drugs to prevent off-target binding to alphaARs, or to elicit a selective interaction with the desired subtype.

Crystal structure of the alpha1B-adrenergic receptor reveals molecular determinants of selective ligand recognition.,Deluigi M, Morstein L, Schuster M, Klenk C, Merklinger L, Cridge RR, de Zhang LA, Klipp A, Vacca S, Vaid TM, Mittl PRE, Egloff P, Eberle SA, Zerbe O, Chalmers DK, Scott DJ, Pluckthun A Nat Commun. 2022 Jan 19;13(1):382. doi: 10.1038/s41467-021-27911-3. PMID:35046410^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.