A third motif involves the toggle switch and consists of

A third motif involves the toggle switch and consists of the conserved FxxCWxP sequence in TM6 of class A GPCRs (Hofmann et al., 2009, Rosenbaum et al., 2009). Rotamerization of Trp in combination with a kink caused by Pro facilitates the outward movement of TM6 upon activation (Hofmann et al., 2009, Rosenbaum et al., 2009). A conserved Trp residue is found at the corresponding position in class C receptors, and lines the allosteric site in mGlu1 and mGlu5 TM structures (Christopher et al., 2015, Dore et al., 2014, Wu et al., 2014). The conformation of this Trp residue is a determining factor of the size and shape of the allosteric pocket (Christopher et al., 2015, Dore et al., 2014). During activation of class C GPCRs, the contraction of extracellular structure would force the TM domains to rearrange within the dimer. FRET measurements reveal a shift in the orientation and distance between TM domains in both GABAB and mGlu receptors by tracking the intersubunit movement between intracellular loops (Hlavackova et al., 2012, Marcaggi et al., 2009, Matsushita et al., 2010, Tateyama et al., 2004) and between extracellular loops (Lecat-Guillet et al., 2017). In addition, a recent study uses a combination of disulfide crosslinking and FRET techniques to determine the location of dimer interfaces within the mGlu Olanzapine receptor TM domain (Xue et al., 2015). It shows that covalently crosslinking TM4 and TM5 together results in a non-functioning receptor, suggesting that TM4 and TM5 form a dimer interface in the inactive state. On the other hand, a receptor with a permanently attached TM6 pair displays constitutive activity, indicating that TM6 mediates dimer interaction in the active state. Taken together, a common theme of class C GPCR activation involves agonist-induced closure of extracellular VFT followed by union of membrane-proximal domains. These changes are accompanied by a decrease in separation between the C-terminal ends of the extracellular domains, which subsequently modify the relationship between the TM regions for receptor activation. In addition, an intermediate state has been detected in mGlu receptor by FRET, and likely involves one agonist-bound VFT (Vafabakhsh et al., 2015). It remains to be seen whether this is a universal feature of class C GPCRs.
Conclusion The recent structures of GABAB receptor components combined with extensive functional studies have improved our understanding of the relationship between ligand binding and conformational changes in the heterodimeric complex. To visualize how these events are eventually translated into transmembrane signaling, we will ultimately need three-dimensional structures of the full-length receptor in multiple conformational states, and in complex with auxiliary subunits and downstream signaling molecules. The insights obtained from these studies will aid the design of valuable therapeutic agents for GABAB receptor-related neurological diseases.
Funding This work was supported by the National Institute of Health [R01GM088454, R01GM112973] and American Heart Association [SDG0835183N, 15GRNT25420002]. QRF was an Irma Hirschl Career Scientist, Pew Scholar, McKnight Scholar and Schaefer Scholar.
Acknowledgement
Anion receptors are of interest because of their applications in chemistry, biology and environmental sciences [,]. Therefore, considerable efforts have been devoted to design, synthesis and assessment of different types of the anion receptors. Recently, the researchers have focused on the design and synthesis of neutral receptors that interact with the anions, selectively [, , ]. The function of many of the anion receptors is mainly based on non-covalent interactions such as hydrogen bonding interactions [,]; therefore, the interaction between the receptor and the anion is usually weak. However, some anion receptors with higher binding energies have also been proposed [,]. Boron is known as a strong Lewis acid due to its empty p orbital, hence, many boron-based anion receptors have been reported []. To enhance the anion affinity of these anion receptors, the bidentate diboranes have also been proposed [,]. Another strategy is substitution of electron withdrawing groups to the boron-based anion receptors. Tris(perfluorophenyl)borane is one of the strongest boron-based anion receptors with F affinity of 406 kJ/mol [].