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

The α₁-adrenoceptor (α₁AR) is a critically important class of G protein-coupled receptors, comprising 3 subtypes: α_1AAR, α_1BAR, and α_1DAR. Currently, drugs targeting α₁AR have been used in the treatment of various diseases. Notably, antagonists of α₁AR play a pivotal role in the management of benign prostatic hyperplasia. In recent years, researchers have developed selective antagonists for the α_1AAR subtype that have a minimal impact on blood pressure for the treatment of benign prostatic hyperplasia. 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 α₁AR-selective antagonist doxazosin and the α_1AAR subtype-selective antagonist silodosin in complex with α_1AAR, demonstrating that M292^6.55 and V185^5.39 are key residues that confer subtype selectivity to silodosin. In addition, modifications to α_1BAR enhanced silodosin's inhibitory efficacy against α_1BAR. These findings deepen our understanding of the recognition patterns of α_1AAR antagonists, revealing the molecular principles underlying the selective binding of silodosin to α_1AAR and promoting further research and development of subtype-selective drugs targeting α_1AAR.