The Ca2+-sensing receptor and the pocketome: comparing nature’s complexity with human intervention in receptor modulation

In a recent paper published in Nature, 1 the relatively understudied Ca 2+ -sensing receptor (CaSR) within the G protein-coupled receptor (GPCR) family C, gained attention due to pioneering research led by Georgios Skiniotis from Stanford University, with four shared first authors.Their international team unveiled cryogenic electron microscopy (cryo-EM) structures of the human CaSR, embedded in lipid nanodiscs, elucidating its interaction with the calcimimetic drug cinacalcet, G i or G q proteins and provided structural insights into gain or loss of function mutations associated with human diseases. 1imilar to other family C receptors such as metabotropic glutamate (mGlu) or γ-aminobutyric acid B (GABA B ) receptors, the CaSR features a large N-terminal extracellular ligand-binding domain alongside the classical seven transmembrane (7TM) helical domain.However, until now, its activation mechanism remained unknown, evoking questions about its similarity to other class C GPCRs. 2 In their recent publication, He et al. reveal that the CaSR forms an asymmetrically activated dimer, mirroring the activation pattern observed for other class C family members. 1,2In this dimer, G proteins selectively engage one of the two protomers, inducing significant rearrangements within the intracellular loop (ICL) 2, in contrast to the major rearrangements observed in TM6 and ICL3 commonly seen in many class A family GPCRs.This structural insight clarifies why FRET-based conformational change sensors for family C GPCRs specifically require fluorophore insertion in ICL2 rather than ICL3. 3 Nevertheless, receptor activation is not solely induced by agonist binding, but requires G protein interaction to achieve full activation, a mechanistic feature shared across different GPCR families, as exemplary observed for class A receptors.Here, the authors clearly elucidate that the coupling selectivity towards G i or G q proteins is determined by differential structural rearrangements in the ICL2 along with the receptor C-terminus, collectively forming the respective binding interface for the G protein. 1 Additionally, the binding of a G protein induces a distinct asymmetric rearrangement of the dimer interface compared to the inactive receptor dimer.Recent findings suggest that such dimer rearrangements are temporally positioned between the steps of G protein binding and activation. 4It is tempting to speculate that such kinetic orders might be a common feature among dimeric GPCRs.In the complex structures of the CaSR with G i or G q protein, multiple binding sites for different ligands are resolved, ranging from the orthosteric ligand-binding Venus flytrap domain to FUNDING