Coupling ligand structure to specific conformational switches in the β2-adrenoceptor

Xiaojie Yao, Charles Parnot, Xavier Deupi, Venkata R.P. Ratnala, Gayathri Swaminath, David Farrens, Brian Kobilka

Research output: Contribution to journalArticle

271 Scopus citations

Abstract

G protein-coupled receptors (GPCRs) regulate a wide variety of physiological functions in response to structurally diverse ligands ranging from cations and small organic molecules to peptides and glycoproteins. For many GPCRs, structurally related ligands can have diverse efficacy profiles. To investigate the process of ligand binding and activation, we used fluorescence spectroscopy to study the ability of ligands having different efficacies to induce a specific conformational change in the human β2- adrenoceptor (β2-AR). The 'ionic lock' is a molecular switch found in rhodopsin-family GPCRs that has been proposed to link the cytoplasmic ends of transmembrane domains 3 and 6 in the inactive state. We found that most partial agonists were as effective as full agonists in disrupting the ionic lock. Our results show that disruption of this important molecular switch is necessary, but not sufficient, for full activation of the β2-AR.

Original languageEnglish (US)
Pages (from-to)417-422
Number of pages6
JournalNature Chemical Biology
Volume2
Issue number8
DOIs
StatePublished - Aug 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Yao, X., Parnot, C., Deupi, X., Ratnala, V. R. P., Swaminath, G., Farrens, D., & Kobilka, B. (2006). Coupling ligand structure to specific conformational switches in the β2-adrenoceptor. Nature Chemical Biology, 2(8), 417-422. https://doi.org/10.1038/nchembio801