As an introduction, some principles of nuclear spin physics applying to studies of integral membrane proteins (IMP) will be reviewed. Applications of resulting nuclear magnetic resonance (NMR) techniques will then be illustrated with studies of G-protein-coupled receptors (GPCR). GPCRs are targets for more than 30% of the presently available prescription drugs approved for use in human medicine. The family of GPCRs are IMPs located on the cell surface, where they mediate a wide range of intercellular communications. Binding of a variety of drug molecules to the extracellular GPCR surface elicits intracellular signaling by conformational changes in locations at distances of more than 30 A from the Iigand binding site. We use solution NMR techniques to collect data on the associated allostery-related conformational equilibria and rate processes. Specifically, 19F NMR spectroscopy and site-specific mutagenesis is used to monitor equilibria between inactive and activated states of GPCRs, which affords novel insights into the pathways for signaling to intracellular partner proteins.
Liu, J.J., Horst, R., Katritch, V., Stevens, R.C. and Wüthrich, K. (2012) Science 335, 1106-1110.
Biased signaling pathways in ß2-adrenergic receptor characterized by 19 F-NMR.
Stevens, R.C., Cherezov, V., Katritch, V., Abagyan. R., Kuhn, P., Rosen, H. and Wüthrich, K. (2013) Nat. Rev.Drug Disc. 12, 1-10.
The GPCR Network: a large-scale collaboration to determine human GPCR structure and function.