Coupling ligand structure to specific conformational switches in the beta2-adrenoceptor - PubMed

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• PMID: 16799554
• DOI: 10.1038/nchembio801

Coupling ligand structure to specific conformational switches in the beta2-adrenoceptor

Xiaojie Yao et al. Nat Chem Biol. 2006 Aug.

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 beta2-adrenoceptor (beta2-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 beta2-AR.

Comment in

• Switching modes for G protein-coupled receptor activation.

  Vilardaga JP. Vilardaga JP. Nat Chem Biol. 2006 Aug;2(8):395-6. doi: 10.1038/nchembio0806-395. Nat Chem Biol. 2006. PMID: 16850011 No abstract available.

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