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TitleMolecular Mechanism of the βAR Agonist Activity of a β-Blocker.
Journal, issue, pagesChempluschem, Vol. 89, Issue 12, Page e202400288, Year 2024
Publish dateSep 18, 2024
AuthorsShuang Zheng / Shuhao Zhang / Shengjie Dai / Kai Chen / Kaixuan Gao / Xiaoou Sun / Bin Lin / Xiangyu Liu /
PubMed AbstractDevelopment 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 ...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.
External linksChempluschem / PubMed:39046191
MethodsEM (single particle)
Resolution2.34 - 2.76 Å
Structure data

60628

9ijd

EMDB-60628, PDB-9ijd:
Carazolol-activated human beta3 adrenergic receptor
Method: EM (single particle) / Resolution: 2.76 Å

60629

9ije

EMDB-60629, PDB-9ije:
Epinephrine-activated human beta3 adrenergic receptor
Method: EM (single particle) / Resolution: 2.34 Å

Chemicals

ChemComp-CAU:
(2S)-1-(9H-Carbazol-4-yloxy)-3-(isopropylamino)propan-2-ol

ChemComp-ALE:
L-EPINEPHRINE / medication, hormone*YM

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
  • lama glama (llama)
  • bos taurus (domestic cattle)
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / Complex / beta3AR / MEMBRANE PROTEIN-IMMUNE SYSTEM complex

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