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

## TL;DR

This study reveals how specific drugs bind to a type of receptor in the body, offering insights for developing better medications with fewer side effects.

## Contribution

The paper identifies key molecular residues responsible for the selectivity of silodosin to the α1AAR subtype.

## Key findings

- Cryo-EM structures show M2926.55 and V1855.39 are critical for silodosin's subtype selectivity.
- Modifications to α1BAR improved silodosin's inhibitory efficacy against this subtype.
- The findings provide molecular principles for designing more selective α1AAR-targeting drugs.

## Abstract

The α1-adrenoceptor (α1AR) is a critically important class of G protein–coupled receptors, comprising 3 subtypes: α1AAR, α1BAR, and α1DAR. 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 α1AAR 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 α1AAR subtype–selective antagonist silodosin in complex with α1AAR, demonstrating that M2926.55 and V1855.39 are key residues that confer subtype selectivity to silodosin. In addition, modifications to α1BAR enhanced silodosin's inhibitory efficacy against α1BAR. These findings deepen our understanding of the recognition patterns of α1AAR antagonists, revealing the molecular principles underlying the selective binding of silodosin to α1AAR and promoting further research and development of subtype-selective drugs targeting α1AAR.