Abstract
Abstractα-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 α1BAR bound to the inverse agonist (+)-cyclazosin, enabled by the fusion to a DARPin crystallization chaperone. The α1BAR structure allows the identification of two unique secondary binding pockets. By structural comparison of α1BAR with α2ARs, and by constructing α1BAR-α2CAR chimeras, we identify residues 3.29 and 6.55 as key determinants of ligand selectivity. Our findings provide a basis for discovery of α1BAR-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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference86 articles.
1. Bylund, D. B. et al. International union of pharmacology nomenclature of adrenoceptors. Pharmacol. Rev. 46, 121–136 (1994).
2. Hieble, J. P. et al. International union of pharmacology. X. recommendation for nomenclature of α1-adrenoceptors: consensus update. Pharmacol. Rev. 47, 267–270 (1995).
3. Pupo, A. S. & Minneman, K. P. Adrenergic pharmacology: focus on the central nervous system. CNS Spectr. 6, 656–662 (2001).
4. Finch, A. M. et al. In The Adrenergic Receptors: In The 21st Century (ed. Perez, D. M.) 25–147 (Humana Press, 2005).
5. Fuentes, A. V., Pineda, M. D. & Venkata, K. C. N. Comprehension of top 200 prescribed drugs in the US as a resource for pharmacy teaching, training and practice. Pharmacy 6, 43 (2018).
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