Conformational changes involved in G-protein-coupled-receptor activation.
Little is known about the nature of the conformational changes that convert G-protein-coupled receptors (GPCRs), which bind diffusible ligands, from their resting into their active states. To gain structural insight into this process, various laboratories have used disulfide cross-linking strategies involving cysteine-substituted mutant GPCRs. Several recent disulfide cross-linking studies using the M(3) muscarinic acetylcholine receptor as a model system have led to novel insights into the conformational changes associated with the activation of this prototypical class I GPCR. These structural changes are predicted to involve multiple receptor regions, primarily distinct segments of transmembrane helices III, VI and VII and helix 8. Given the high degree of structural homology found among most GPCRs, it is likely that these findings will be of considerable general relevance. A better understanding of the molecular mechanisms underlying GPCR activation might lead to novel strategies aimed at modulating GPCR function for therapeutic purposes.
Wess
Jürgen
J
Molecular Signaling Section and Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. jwess@helix.nih.gov
Han
Sung-Jun
SJ
Kim
Soo-Kyung
SK
Jacobson
Kenneth A
KA
Li
Jian Hua
JH
D000818:Animals; D001665:Binding Sites; D003545:Cysteine / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D043587:Receptor, Muscarinic M3 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*
D004220:Disulfides; D008024:Ligands; D043587:Receptor, Muscarinic M3; D003545:Cysteine