| Title: |
Crystal structure of the α$_{1B}$-adrenergic receptor reveals molecular determinants of selective ligand recognition |
| Authors: |
Deluigi, Mattia; Morstein, Lena; Schuster, Matthias; Klenk, Christoph; Merklinger, Lisa; Cridge, Riley R; de Zhang, Lazarus A; Klipp, Alexander; Vacca, Santiago; Vaid, Tasneem M; Mittl, Peer R E; Egloff, Pascal; Eberle, Stefanie A; Zerbe, Oliver; Chalmers, David K; Scott, Daniel J; Plückthun, Andreas |
| Source: |
Deluigi, Mattia; Morstein, Lena; Schuster, Matthias; Klenk, Christoph; Merklinger, Lisa; Cridge, Riley R; de Zhang, Lazarus A; Klipp, Alexander; Vacca, Santiago; Vaid, Tasneem M; Mittl, Peer R E; Egloff, Pascal; Eberle, Stefanie A; Zerbe, Oliver; Chalmers, David K; Scott, Daniel J; Plückthun, Andreas (2022). Crystal structure of the α$_{1B}$-adrenergic receptor reveals molecular determinants of selective ligand recognition. Nature Communications, 13(1):382. |
| Publisher Information: |
Nature Publishing Group |
| Publication Year: |
2022 |
| Collection: |
University of Zurich (UZH): ZORA (Zurich Open Repository and Archive |
| Subject Terms: |
Department of Biochemistry; 570 Life sciences; biology; 610 Medicine & health |
| 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$_{1B}$AR bound to the inverse agonist (+)-cyclazosin, enabled by the fusion to a DARPin crystallization chaperone. The α$_{1B}$AR structure allows the identification of two unique secondary binding pockets. By structural comparison of α$_{1B}$AR with α$_{2}$ARs, and by constructing α$_{1B}$AR-α$_{2C}$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$_{1B}$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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
2041-1723 |
| Relation: |
https://www.zora.uzh.ch/id/eprint/213471/1/deLuigi_et_al._2022.pdf; info:pmid/35046410; urn:issn:2041-1723 |
| Availability: |
https://www.zora.uzh.ch/id/eprint/213471/; https://www.zora.uzh.ch/id/eprint/213471/1/deLuigi_et_al._2022.pdf |
| Rights: |
info:eu-repo/semantics/openAccess ; Creative Commons: Attribution 4.0 International (CC BY 4.0) ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.6CD74E69 |
| Database: |
BASE |