受体
结合位点
生物
配体(生物化学)
血浆蛋白结合
融合蛋白
计算生物学
兴奋剂
细胞生物学
化学
生物化学
基因
重组DNA
作者
Mattia Deluigi,Lena Morstein,Matthias Schuster,Christoph Klenk,L. Merklinger,Riley R. Cridge,Lazarus A. de Zhang,A. Klipp,Santiago Vacca,Tasneem M. Vaid,Peer R. E. Mittl,Pascal Egloff,S.A. Eberle,Oliver Zerbe,David K. Chalmers,Daniel J. Scott,Andreas Plückthun
标识
DOI:10.1038/s41467-021-27911-3
摘要
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 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.
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