7B6W
Crystal structure of the human alpha1B adrenergic receptor in complex with inverse agonist (+)-cyclazosin
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Summary for 7B6W
| Entry DOI | 10.2210/pdb7b6w/pdb |
| Descriptor | Alpha-1B adrenergic receptor,alpha1B adrenergic receptor,Alpha-1B adrenergic receptor,alpha1B adrenergic receptor,Alpha-1B adrenergic receptor,alpha1B adrenergic receptor,Alpha-1B adrenergic receptor,alpha1B adrenergic receptor, [(4~{a}~{R},8~{a}~{S})-4-(4-azanyl-6,7-dimethoxy-quinazolin-2-yl)-2,3,4~{a},5,6,7,8,8~{a}-octahydroquinoxalin-1-yl]-(furan-2-yl)methanone (2 entities in total) |
| Functional Keywords | gpcr-ligand complex, alpha1b adrenergic receptor, cyclazosin, inverse agonist, membrane protein |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 1 |
| Total formula weight | 50880.41 |
| Authors | Deluigi, M.,Morstein, L.,Hilge, M.,Schuster, M.,Merklinger, L.,Klipp, A.,Scott, D.J.,Plueckthun, A. (deposition date: 2020-12-08, release date: 2022-01-12, Last modification date: 2024-11-20) |
| Primary citation | Deluigi, M.,Morstein, L.,Schuster, M.,Klenk, C.,Merklinger, L.,Cridge, R.R.,de Zhang, L.A.,Klipp, A.,Vacca, S.,Vaid, T.M.,Mittl, P.R.E.,Egloff, P.,Eberle, S.A.,Zerbe, O.,Chalmers, D.K.,Scott, D.J.,Pluckthun, A. Crystal structure of the alpha 1B -adrenergic receptor reveals molecular determinants of selective ligand recognition. Nat Commun, 13:382-382, 2022 Cited by PubMed 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 αAR bound to the inverse agonist (+)-cyclazosin, enabled by the fusion to a DARPin crystallization chaperone. The αAR structure allows the identification of two unique secondary binding pockets. By structural comparison of αAR with αARs, and by constructing αAR-αAR chimeras, we identify residues 3.29 and 6.55 as key determinants of ligand selectivity. Our findings provide a basis for discovery of αAR-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. PubMed: 35046410DOI: 10.1038/s41467-021-27911-3 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.873 Å) |
Structure validation
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