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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)3205-3215.e5
JournalMolecular Cell
Volume81
Issue number15
DOIs
Publication statusPublished - 2021 Aug 5

Keywords

  • adrenergic receptor
  • cryo-EM
  • G-protein-coupled receptor
  • ligand selectivity
  • mirabegron
  • NanoBiT-G-protein dissociation assay
  • overactive bladder
  • receptor activation
  • βAR

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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