Chapter 13: Characterizing Conformational Diversity of G Protein-coupled Receptors by Solution NMR Spectroscopy
Published:17 Aug 2022
F. Wu, F. Bumbak, M. H. Tanipour, K. Asadollahi, T. M. Vaid, A. Sethi, ... P. R. Gooley, in NMR Spectroscopy for Probing Functional Dynamics at Biological Interfaces, ed. A. Bhunia, H. S. Atreya, and N. Sinha, The Royal Society of Chemistry, 2022, ch. 13, pp. 346-382.
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G protein-coupled receptors are the largest family of integral membrane proteins in humans that have roles in almost all physiological processes. The binding of extracellular ligands allosterically modulates the intracellular interaction of the GPCR with transducer proteins such as G proteins and arrestins. This allosteric coupling operates via a network of conserved microswitches to adjust the equilibrium of active, intermediate and inactive states of the GPCR. Crystallography and cryo-electron microscopy have determined the structures of many active and inactive state GPCRs, while solution-state methods such as NMR spectroscopy inform on the dynamics of additional states and their role in signalling. In addition, solution NMR spectroscopy is providing insight into the pathways and mechanisms of ligand binding, including disordered peptides, to GPCRs. This chapter reviews the challenges in preparing GPCRs for solution NMR data collection, the knowledge gained about the conformational landscapes and ligand binding to GPCRs.