7XJH

Isoproterenol-activated dog beta3 adrenergic receptor

Summary for 7XJH

• Entry DOI: 10.2210/pdb7xjh/pdb
• EMDB information: 33227
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 147255.93

Authors

Shihoya, W.,Nureki, O. (deposition date: 2022-04-18, release date: 2022-05-04, Last modification date: 2024-10-23)

Primary citation

Nagiri, C.,Kobayashi, K.,Tomita, A.,Kato, M.,Kobayashi, K.,Yamashita, K.,Nishizawa, T.,Inoue, A.,Shihoya, W.,Nureki, O.
Cryo-EM structure of the beta 3-adrenergic receptor reveals the molecular basis of subtype selectivity.
Mol.Cell, 81:3205-3215.e5, 2021

PubMed Abstract: The β-adrenergic receptor (βAR) 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 βAR-G signaling complex with the selective agonist mirabegron, a first-in-class drug for OAB. Comparison of this structure with the previously reported βAR and βAR structures reveals a receptor activation mechanism upon mirabegron binding to the orthosteric site. Notably, the narrower exosite in βAR 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.

PubMed: 34314699
DOI: 10.1016/j.molcel.2021.06.024

Experimental method

ELECTRON MICROSCOPY (3.3 Å)