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    • crth2 receptor The known crystal structures of

    2022-11-09

    The known crystal structures of class C GPCR VFTs do not include attached TM domains, therefore current conformational data may not accurately reflect the dynamics of extracellular domains in full-length receptors. Nevertheless, compelling mechanisms of signal transduction can still be postulated. Structural comparison indicates that GABAB and CaS receptors share a common agonist-dependent activation mechanism, although the design of CaS crth2 receptor is typically homodimeric (Geng et al., 2013, Geng et al., 2016). First, the extracellular portions of both receptors dimerize through their N-terminal LB1 domains (Fig. 5A and B). The LB1-LB1 dimer interface remains relatively static throughout the activation process since agonist binding only induces a small 5°-rotation in the orientation of this interface (Fig. 5A and B). The near-constant angle between LB1 domains in GABAB receptor heterodimer is further evidenced in recent FRET studies of full-length receptor, where a negligible change in distance between the N-termini of GABAB1 and GABAB2 was detected (Lecat-Guillet et al., 2017, Scholler et al., 2017). These observations suggest that the functional role of LB1-LB1 interaction in GABAB and CaS receptors is to facilitate dimerization between receptor subunits. Second, receptor activation is associated with a wider range of movements between the membrane proximal domains. In the GABAB receptor heterodimer, the LB2 domains of both subunits approach each other until a critical heterodimer interface forms (Fig. 5A). Functional analysis indicates that development of the LB2-LB2 interface is both necessary and sufficient to initiate G protein coupling (Geng et al., 2013, Rondard et al., 2008). CaS receptor enters a similar arrangement, but its interface is more extensive (Fig. 5B). CaS receptor possesses a cysteine-rich (CR) domain immediately below the LB2 domain, as do all class C GPCRs except GABAB receptor (Kniazeff et al., 2011, Pin and Bettler, 2016). In the active state, the LB2 domain of each CaS receptor protomer forms contacts with residues on the LB1, LB2, and CR of the other protomer. Contraction of LB2 domains toward each other causes the CR domains to dimerize as well. The CR domain mediates signal transduction from the VFT to the TM domain, and the CR-CR interface is mandatory for CaS receptor activation (Hauache et al., 2000, Hu et al., 2000). The mGlu group of receptors consists of eight subtypes, and has been the best-studied of all class C GPCRs (Niswender and Conn, 2010, Pin and Acher, 2002). Extensive knowledge of mGlu receptor conformational dynamics have been obtained through x-ray crystallography and FRET spectroscopy (Christopher et al., 2015, Dore et al., 2014, Doumazane et al., 2013, Hlavackova et al., 2012, Huang et al., 2011, Kunishima et al., 2000, Levitz et al., 2016, Marcaggi et al., 2009, Muto et al., 2007, Olofsson et al., 2014, Scholler et al., 2017, Tateyama et al., 2004, Tsuchiya et al., 2002, Vafabakhsh et al., 2015, Wu et al., 2014, Xue et al., 2015). The mGlu receptors differ from GABAB and CaS receptors in the role of LB1-LB1 interaction during receptor activation. Crystallographic analysis finds that transition between the resting and active configurations causes a 70°-rotation in the LB1-LB1 homodimer interface of mGlu receptors (Kunishima et al., 2000, Muto et al., 2007, Tsuchiya et al., 2002) (Fig. 5C). This large relative movement of mGlu LB1 domains is independently detected in FRET studies where a donor or acceptor fluorophore is tagged onto the N-terminal end of each protomer (Doumazane et al., 2013, Levitz et al., 2016, Olofsson et al., 2014, Scholler et al., 2017, Vafabakhsh et al., 2015). The inactive state produces a high FRET level, while the active state shows low FRET efficiency. These findings indicate an increase in the distance between the N-termini of protomers upon receptor activation. The contrast in LB1-LB1 movement of mGlu and GABAB receptors may be explained by the different properties of their dimer interfaces. The mGlu LB1 domains are largely joined together by hydrophobic contacts (Kunishima et al., 2000). GABAB receptor, however, employs hydrogen bonds in addition to nonpolar contacts (Geng et al., 2013). The combination of ionic and hydrophobic interactions may have limited reorientation of the LB1-LB1 interface in GABAB receptor. On the other hand, the LB1-LB1 interface of CaS receptor may be locked through additional interaction that is unique to this receptor. In addition to the interface formed by two central LB1 helices, as in mGlu and GABAB receptors, the LB1-LB1 homodimer of CaS receptor is held in place by an “embrace” extended from an arm-like long loop of each subunit to its partner (Geng et al., 2016).