Molecular mechanism of antagonist recognition and regulation of the α1A-adrenoceptor

The α 1 -adrenoceptor (α 1 AR) is a critically important class of G protein-coupled receptors (GPCRs), comprising three subtypes: α 1A AR, α 1B AR, and α 1D AR. Currently, drugs targeting α 1 AR have been used in the treatment of various diseases. Notably, antagonists of α 1 AR play a pivotal role in the management of benign prostatic hyperplasia (BPH). In recent years, researchers have developed selective antagonists for the α 1A AR subtype that have a minimal impact on blood pressure for the treatment of BPH. However, these agents still exhibit certain side effects, necessitating the continuous development of new medications to mitigate adverse reactions while achieving more precise regulation. We report the cryo-EM structures of the α 1 AR selective antagonist doxazosin and the α 1A AR subtype selective antagonist silodosin in complex with α 1A AR, demonstrating that M292 6.55 and V185 5.39 are key residues that confer subtype selectivity to silodosin. Additionally, modifications to α 1B AR enhanced silodosin's inhibitory efficacy against α 1B AR. These findings deepen our understanding of the recognition patterns of α 1A AR antagonists, revealing the molecular principles underlying the selective binding of silodosin to α 1A AR and promoting further research and development of subtype selective drugs targeting α 1A AR.