Letter abstract
Nature Chemical Biology 2, 417 - 422 (2006)
Published online: 25 June 2006 | doi:10.1038/nchembio801
Coupling ligand structure to specific conformational switches in the 
2-adrenoceptor
Xiaojie Yao1,3, Charles Parnot1,3, Xavier Deupi1, Venkata R P Ratnala1, Gayathri Swaminath1, David Farrens2 & Brian Kobilka1
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 
2-adrenoceptor (2-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 state1, 2, 3. 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 2-AR.
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, Palo Alto, California 94305, USA.
- Departments of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Drive, Portland, Oregon 97201-3098, USA.
- These authors contributed equally to this work.
Correspondence to: Brian Kobilka1 e-mail: kobilka@stanford.edu
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