Abstract
Although family B G protein-coupled receptors (GPCRs) contain only 15 members, they play key roles in transmembrane signal transduction of hormones. Family B GPCRs are drug targets for developing therapeutics for diseases ranging from metabolic to neurological disorders. Despite their importance, the molecular mechanism of activation of family B GPCRs remains largely unexplored due to the challenges in expression and purification of functional receptors to the quantity for biophysical characterization. Currently, there is no crystal structure available of a full-length family B GPCR. However, structures of key domains, including the extracellular ligand binding regions and seven-helical transmembrane regions, have been solved by X-ray crystallography and NMR, providing insights into the mechanisms of ligand recognition and selectivity, and helical arrangements within the cell membrane. Moreover, biophysical and biochemical methods have been used to explore functions, key residues for signaling, and the kinetics and dynamics of signaling processes. This review summarizes the current knowledge of the signal transduction mechanism of family B GPCRs at the molecular level and comments on the challenges and outlook for mechanistic studies of family B GPCRs.
Highlights
Gprotein-coupled receptors (GPCRs), which form the largest protein superfamily of the vertebrate genome, play an important role in signal transduction by detecting extracellular stimuli and activating intracellular downstream pathways (Figure 1; Fredriksson et al, 2003)
It is widely accepted that the peptide hormones interact with family B GPCRs following the “two-domain” model, in which the peptide hormone’s Cterminus binds to their cognate receptor’s N-terminal domain and the N-terminus binds to the receptor’s juxtamembrane and transmembrane domains (Figure 2)
It is worth noting that the crystal structure of CRF1R in complex with CP-376395 uncovered an unusual, small-molecule binding pocket that is deep in the intracellular half of the receptor transmembrane domain (TMD), over 15 Å away from the any ligand-binding site in the known family A GPCR structures (Figures 11A,C; Okada et al, 2004; Cherezov et al, 2007; Chien et al, 2010; Wu et al, 2010; Shimamura et al, 2011; Hollenstein et al, 2013)
Summary
Gprotein-coupled receptors (GPCRs), which form the largest protein superfamily of the vertebrate genome, play an important role in signal transduction by detecting extracellular stimuli and activating intracellular downstream pathways (Figure 1; Fredriksson et al, 2003). All GPCRs share a common seven-transmembrane topology, and mediate cellular responses through interactions with a variety of extracellular signals. These extracellular signals range from photons and small molecules to hormones and proteins, indicating the structural and functional diversity of over 800 different GPCRs (Lagerstrom and Schioth, 2008). Since the ligand binding sites are highly specific, GPCRs have been heavily exploited as drug targets. They are the targets for over 40% of the current pharmaceutical drugs on the market with an estimated global sales of ∼$85 billion (Stevens et al, 2013). Most drugs developed against GPCRs target family A receptors, family B GPCRs are becoming increasingly attractive drug targets, especially for treatment of metabolic diseases
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