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

Mattia Deluigi, Lena Morstein, Matthias Schuster, Christoph Klenk, Lisa Merklinger, Riley R. Cridge, Lazarus A. Zhang, Alexander Klipp, Santiago Vacca, Tasneem M. Vaid, Peer R. E. Mittl, Pascal Egloff, Stefanie A. Eberle, Oliver Zerbe, David K. Chalmers, Daniel J. Scott () and Andreas Plückthun ()
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Mattia Deluigi: University of Zurich
Lena Morstein: University of Zurich
Matthias Schuster: University of Zurich
Christoph Klenk: University of Zurich
Lisa Merklinger: University of Zurich
Riley R. Cridge: The University of Melbourne
Lazarus A. Zhang: The University of Melbourne
Alexander Klipp: University of Zurich
Santiago Vacca: University of Zurich
Tasneem M. Vaid: Department of Pharmaceutical Sciences, University of Illinois at Chicago
Peer R. E. Mittl: University of Zurich
Pascal Egloff: University of Zurich
Stefanie A. Eberle: University of Zurich
Oliver Zerbe: University of Zurich
David K. Chalmers: Monash University
Daniel J. Scott: The University of Melbourne
Andreas Plückthun: University of Zurich

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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 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.

Date: 2022
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DOI: 10.1038/s41467-021-27911-3

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