Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • Although the LB domains of mGlu receptors have not

    2023-01-18

    Although the LB2 domains of mGlu receptors have not been shown to form an extensive interface during activation, they do draw closer to each other, as demonstrated in crystal structures (Kunishima et al., 2000, Muto et al., 2007, Tsuchiya et al., 2002) and by FRET analysis (Doumazane et al., 2013, Vafabakhsh et al., 2015) (Fig. 5C). Electrostatic interactions between the LB2 domains help stabilize the active conformation (Levitz et al., 2016, Vafabakhsh et al., 2015). Furthermore, the potentially repulsive interaction between an acidic patch on the surface of this domain is alleviated by metal cation in the active state (Tsuchiya et al., 2002). Finally, similar to CaS receptor, a precise association between the CR domains of mGlu receptors has been shown by disulfide crosslinking experiments to lead to full Mesoridazine Besylate sale activation (Huang et al., 2011). The conformational phases of class C TM domains are still at the frontier of research. Our current knowledge is mostly drawn from crystal structures of mGlu1 and mGlu5 TM domains in the inactive state (Christopher et al., 2015, Dore et al., 2014, Wu et al., 2014), as well as FRET analysis on GABAB and mGlu receptors (Hlavackova et al., 2012, Lecat-Guillet et al., 2017, Marcaggi et al., 2009, Matsushita et al., 2010, Tateyama et al., 2004, Xue et al., 2015). Like their class A counterparts, the TM domains of class C GPCRs consist of a seven-helix bundle. Despite many similarities, one major distinction is observed between the solved TM structures of class A and C. The extracellular opening of class C TM domains possesses a narrower ligand-binding cavity than is found in the class A receptors (Christopher et al., 2015, Dore et al., 2014, Wu et al., 2014). This discrepancy stems from an inward shift of TM5 and TM7 helices compared to those in class A structures (Christopher et al., 2015, Dore et al., 2014, Wu et al., 2014). In general, class C TM domains have extracellular regions that lack congruency with class A, as opposed to their intracellular ends which more closely match class A when superimposed (Dore et al., 2014). This may be related to the structural constraints imposed by conserved G protein coupling on the intracellular portion (Dore et al., 2014). The class C GPCRs also possess variants of the structural motifs found in class A receptors that regulate receptor function. One of these conserved motifs is the ionic lock (Hofmann et al., 2009, Rosenbaum et al., 2009). In both receptor families, it involves a salt bridge between a pair of basic and acidic residues that tethers TM3 and TM6 at the intracellular end (Dore et al., 2014, Hofmann et al., 2009, Rosenbaum et al., 2009, Kniazeff et al., 2011, Pin and Bettler, 2016, Wu et al., 2014). The ionic lock maintains the inactive conformation of the TM domain by preventing outward movement of TM6 to expose the G protein-binding site at the intracellular end. The interaction in class A receptors is formed by Arg of the D/ERY motif in TM3 with an acidic residue in TM6 (Hofmann et al., 2009, Rosenbaum et al., 2009). In class C receptors, the salt bridge is observed between a Lys residue in TM3 and a Glu or Asp residue in TM6 (Binet et al., 2007, Christopher et al., 2015, Dore et al., 2014, Pin and Bettler, 2016, Wu et al., 2014). The ionic lock is further secured by a hydrogen bond between the Lys residue and a Ser residue from intracellular loop 1 (Christopher et al., 2015, Dore et al., 2014, Wu et al., 2014). A second conserved motif in class A GPCRs is the NPxxY sequence found at the juncture of TM7 and TM8 (Hofmann et al., 2009, Rosenbaum et al., 2009). The conserved Tyr residue in this motif undergoes conformational change to fill the gap generated by the lateral movement of TM6 during activation (Hofmann et al., 2009, Rosenbaum et al., 2009). The class C receptors feature an analogous motif, F/Y/HxPKxY, at the intracellular end of TM7 (Dore et al., 2014). The conserved Lys and Phe residues in the class C sequence are located at positions equivalent to Tyr in class A motif, and may play a similar role in stabilizing the active conformation (Dore et al., 2014).