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-α2CAR chimeras, we identify residues 3.29 and 6.55 as key determinants of ligand selectivity. Our findings provide a basis for discovery of α1BAR-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.
Highlights
Α-adrenergic receptors are G protein-coupled receptors that regulate vital functions of the cardiovascular and nervous systems
We have recently established the fusion of designed ankyrin repeat protein (DARPin) D12 to transmembrane helix 7 (TM7) of a G protein-coupled receptors (GPCRs) as a tool to facilitate GPCR crystallization[44]
The stabilizing mutations locked the receptor in a signalinginactive state, as evidenced by the lack of agonist-induced Gq signaling compared to wild-type α1BAR (Supplementary Fig. 3a)
Summary
Α-adrenergic receptors (αARs) are G protein-coupled receptors that regulate vital functions of the cardiovascular and nervous systems. Our findings provide a basis for discovery of α1BAR-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. Adrenergic receptors (ARs), or adrenoceptors, are aminergic G protein-coupled receptors (GPCRs) subdivided into nine distinct subtypes in humans1,2—three α1ARs (α1A, α1B, α1D), three α2ARs (α2A, α2B, α2C), and three βARs (β1, β2, β3). There is a lack of truly selective ligands for individual α1AR and α2AR subtypes, which often mediate opposing physiological functions[6,7]. The dearth of fully selective ligands for individual αAR subtypes, for α1BAR, aggravates the scarcity of brainpermeable αAR agents to treat neurological and neuropsychiatric disorders[3,7,8,9,15]. The undesired interaction with α1ARs can result in postural hypotension and related complications as side effects
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