9IJE

Epinephrine-activated human beta3 adrenergic receptor

Summary for 9IJE

• Entry DOI: 10.2210/pdb9ije/pdb
• EMDB information: 60629
• Descriptor: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Camelid antibody VHH fragment, Single-chain Fv16, ... (8 entities in total)
• Functional Keywords: complex, beta3ar, membrane protein/immune system, membrane protein-immune system complex
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 6
• Total formula weight: 161388.16

Authors

Zheng, S.,Zhang, S.,Dai, S.,Chen, K.,Gao, K.,Lin, B.,Liu, X. (deposition date: 2024-06-22, release date: 2024-08-21, Last modification date: 2025-07-23)

Primary citation

Zheng, S.,Zhang, S.,Dai, S.,Chen, K.,Gao, K.,Sun, X.,Lin, B.,Liu, X.
Molecular Mechanism of the beta 3 AR Agonist Activity of a beta-Blocker.
Chempluschem, 89:e202400288-e202400288, 2024

PubMed Abstract: Development of subtype-selective drugs for G protein-coupled receptors poses a significant challenge due to high similarity between subtypes, as exemplified by the three β-adrenergic receptors (βARs). The βAR agonists show promise for treating the overactive bladder or preterm birth, but their potential is hindered by off-target activation of βAR and βAR. Interestingly, several β-blockers, which are antagonists of the βARs and βARs, have been reported to exhibit agonist activity at the βAR. However, the molecular mechanism remains elusive. Understanding the underlying mechanism should facilitate the development of βAR agonists with improved selectivity and reduced off-target effects. In this work, we determined the structures of human βAR in complex with the endogenous agonist epinephrine or with a synthetic βAR agonist carazolol, which is also a high-affinity β-blocker. Structure comparison, mutagenesis studies and molecular dynamics simulations revealed that the differences on the flexibility of D directly contribute to carazolol's distinct activities as an antagonist for the βAR and an agonist for the βAR. The process is also indirectly influenced by the extracellular loops (ECL), especially ECL1. Taken together, these results provide key guidance for development of selective βAR agonists, paving the way for new therapeutic opportunities.

PubMed: 39046191
DOI: 10.1002/cplu.202400288

Experimental method

ELECTRON MICROSCOPY (2.34 Å)