Structural Basis for Activation of the Heterodimeric GABAB Receptor

Structural insights into the activation of human calcium-sensing receptor

“…It suggests that there are three distinct conformations in the process of CaSR activation: inactive, intermediate and active state. The overall structures of CaSR resemble the recently published structures of mGluR5 and GABA B receptor (Kim et al, 2020; Koehl et al, 2019; Mao et al, 2020; Papasergi-Scott et al, 2020; Park et al, 2020; Shaye et al, 2020). These three states are automatically converted.…”

“…The previous study showed that a cysteine cross-linking at residue A824 6.56 led to a constitutively active receptor (Liu et al, 2020). The active mGluR5 (Koehl et al, 2019) and GABA B receptor (Kim et al, 2020; Mao et al, 2020; Papasergi-Scott et al, 2020; Shaye et al, 2020) have the same TM6-TM6 interface as that of CaSR (Figure 6F; Figure 6-figure supplement 2C, D), and it was observed that the TM6 cross-linked mGluR5 and TM6-locked mGluR2 were activated continuously (Koehl et al, 2019; Xue et al, 2015).…”

“…Both inactive and active structures show that there is a bundle structure in the junction region between extracellular and transmembrane domain, which is composed of C-terminal elongated peptide of CRD and the twisted hairpin loop of ECL2 (Figure 7A, B). Unlike mGluR5 and GABA B receptor (Kim et al, 2020; Koehl et al, 2019; Mao et al, 2020; Papasergi-Scott et al, 2020; Park et al, 2020; Shaye et al, 2020), which formed by a twisted three-strand β-sheet, the junction of CaSR is more flexible than that of mGluR5 and GABA B receptor. There is a common interface constitute of residues 759-763 at ECL2 and residues 601-604 at the C-terminal of CRD (Figure 7A), and the interface in the active conformation is more compact than that of in the inactive conformation (Figure 7B).…”

“…First, the rotation of LB2 domain is propagated to the large-scale transition of intersubunit 7TMDs, which leads to rearrangement of 7TMDs interface from TM5-TM6-plane/TM5-TM6-plane interface to TM6-TM6 mediated interface that this contact is considered to be a hallmark of activation in class C GPCR. For the mGluR5 and GABA B receptor, the 7TMDs rearrange from TM5-TM5 interface in the inactive state to TM6-TM6 interface in the active state (Kim et al, 2020; Koehl et al, 2019; Mao et al, 2020; Papasergi-Scott et al, 2020; Park et al, 2020; Shaye et al, 2020). The structure provides important insights for drug design if the TM5-TM6-plane interface of 7TMD is unique for CaSR.…”

“…The recent groundbreaking structural studies of some class C full-length receptors, such as mGluR5 (Koehl et al, 2019) and GABA B receptors (Kim et al, 2020; Mao et al, 2020; Papasergi-Scott et al, 2020; Park et al, 2020; Shaye et al, 2020) by cryo-electron microscopy (cryo-EM) have provided a structural framework through which to unravel the activation mechanisms of class C GPCRs. The crystal structures of the resting and active conformations of CaSR ECD were solved by two different groups (Geng et al, 2016; Zhang et al, 2016).…”