Journal article
Crystal structure of the α1B-adrenergic receptor reveals molecular determinants of selective ligand recognition
M Deluigi, L Morstein, M Schuster, C Klenk, L Merklinger, RR Cridge, LA de Zhang, A Klipp, S Vacca, TM Vaid, PRE Mittl, P Egloff, SA Eberle, O Zerbe, DK Chalmers, DJ Scott, A Plückthun
Nature Communications | Published : 2022
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-α2..
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Awarded by Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Funding Acknowledgements
We thank B. Blattmann and C. Muller-Simmen of the Protein Crystallization Center at the University of Zurich for their support during crystallization, and the staff of the X06SA beamline at the Paul Scherrer Institute for support during X-ray data collection. We thank G. Liechti-Tonarque and D. Barret for their help with protein expression, purification, and characterization, and C. Manatschal for support during the initial phase of refinement of the crystal structure. We thank M. Hilge for data processing and refinement of the crystal structure, and G. Murshudov for his help in the creation of the cyclazosin dictionary. We also would like to acknowledge V. Jameson of the Melbourne Cytometry Platform for assistance with FACS. This work was supported by Schweizerische Nationalfonds grant 31003A_182334 (to A.P.) and Australian National Health and Medical Research Council grants 1081801 and 1137179 (to D.J.S.).