Cryo-EM structure of the β3-adrenergic receptor reveals the molecular basis of subtype selectivity

Chisae Nagiri, Kazuhiro Kobayashi, Atsuhiro Tomita, Masahiko Kato, Kan Kobayashi, Keitaro Yamashita, Tomohiro Nishizawa, Asuka Inoue, Wataru Shihoya, Osamu Nureki

研究成果: Article査読

抄録

The β3-adrenergic receptor (β3AR) is predominantly expressed in adipose tissue and urinary bladder and has emerged as an attractive drug target for the treatment of type 2 diabetes, obesity, and overactive bladder (OAB). Here, we report the cryogenic electron microscopy structure of the β3AR-Gs signaling complex with the selective agonist mirabegron, a first-in-class drug for OAB. Comparison of this structure with the previously reported β1AR and β2AR structures reveals a receptor activation mechanism upon mirabegron binding to the orthosteric site. Notably, the narrower exosite in β3AR creates a perpendicular pocket for mirabegron. Mutational analyses suggest that a combination of both the exosite shape and the amino-acid-residue substitutions defines the drug selectivity of the βAR agonists. Our findings provide a molecular basis for βAR subtype selectivity, allowing the design of more-selective agents with fewer adverse effects.

本文言語English
ページ(範囲)3205-3215.e5
ジャーナルMolecular Cell
81
15
DOI
出版ステータスPublished - 2021 8 5

ASJC Scopus subject areas

  • 分子生物学
  • 細胞生物学

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