Crystal structure of the α <subscript>1B</subscript> -adrenergic receptor reveals molecular determinants of selective ligand recognition. - OpacWWW

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Tytuł:: Crystal structure of the α 1B -adrenergic receptor reveals molecular determinants of selective ligand recognition.
Autorzy:: Deluigi M; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
Morstein L; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
Schuster M; Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
Klenk C; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
Merklinger L; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.; Department of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, 2800 Kgs, Lyngby, Denmark.
Cridge RR; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia.
de Zhang LA; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia.; Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, VIC, 3010, Australia.
Klipp A; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.; Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, CH-8093, Zurich, Switzerland.
Vacca S; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
Vaid TM; Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, USA.
Mittl PRE; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
Egloff P; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
Eberle SA; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
Zerbe O; Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
Chalmers DK; Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
Scott DJ; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia. .; Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, VIC, 3010, Australia. .
Plückthun A; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland. .
Źródło:: Nature communications [Nat Commun] 2022 Jan 19; Vol. 13 (1), pp. 382. Date of Electronic Publication: 2022 Jan 19.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: [London] : Nature Pub. Group
MeSH Terms:: Crystallography, X-Ray*
Receptors, Adrenergic, alpha-1/*chemistry
Binding Sites ; HEK293 Cells ; Humans ; Ligands ; Lipids/chemistry ; Models, Molecular ; Quinazolines/chemistry ; Quinazolines/metabolism ; Quinoxalines/chemistry ; Quinoxalines/metabolism ; Receptors, Adrenergic, alpha-2/chemistry
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Substance Nomenclature:: 0 (Ligands)
0 (Lipids)
0 (Quinazolines)
0 (Quinoxalines)
0 (Receptors, Adrenergic, alpha-1)
0 (Receptors, Adrenergic, alpha-2)
139953-73-4 (cyclazosin)
Entry Date(s):: Date Created: 20220120 Date Completed: 20220215 Latest Revision: 20221024
Update Code:: 20240105
PubMed Central ID:: PMC8770593
DOI:: 10.1038/s41467-021-27911-3
PMID:: 35046410
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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.
(© 2022. The Author(s).)

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Crystal structure of the α 1B -adrenergic receptor reveals molecular determinants of selective ligand recognition.