9AVG

Structure of human calcium-sensing receptor in complex with chimeric Gs (miniGis) protein in nanodiscs

This is a non-PDB format compatible entry.

Summary for 9AVG

• Entry DOI: 10.2210/pdb9avg/pdb
• EMDB information: 43901
• Descriptor: Isoform 1 of Extracellular calcium-sensing receptor, 3-(2-chlorophenyl)-N-[(1R)-1-(3-methoxyphenyl)ethyl]propan-1-amine, CHOLESTEROL HEMISUCCINATE, ... (12 entities in total)
• Functional Keywords: calcium-sensing receptor, g-protein-coupled receptor, g protein, signal transduction, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 285944.48

Authors

Zuo, H.,Park, J.,Frangaj, A.,Ye, J.,Lu, G.,Manning, J.J.,Asher, W.B.,Lu, Z.,Hu, G.,Wang, L.,Mendez, J.,Eng, E.,Zhang, Z.,Lin, X.,Grasucci, R.,Hendrickson, W.A.,Clarke, O.B.,Javitch, J.A.,Conigrave, A.D.,Fan, Q.R. (deposition date: 2024-03-02, release date: 2024-04-17, Last modification date: 2024-10-30)

Primary citation

Zuo, H.,Park, J.,Frangaj, A.,Ye, J.,Lu, G.,Manning, J.J.,Asher, W.B.,Lu, Z.,Hu, G.B.,Wang, L.,Mendez, J.,Eng, E.,Zhang, Z.,Lin, X.,Grassucci, R.,Hendrickson, W.A.,Clarke, O.B.,Javitch, J.A.,Conigrave, A.D.,Fan, Q.R.
Promiscuous G-protein activation by the calcium-sensing receptor.
Nature, 629:481-488, 2024

PubMed Abstract: The human calcium-sensing receptor (CaSR) detects fluctuations in the extracellular Ca concentration and maintains Ca homeostasis. It also mediates diverse cellular processes not associated with Ca balance. The functional pleiotropy of CaSR arises in part from its ability to signal through several G-protein subtypes. We determined structures of CaSR in complex with G proteins from three different subfamilies: G, G and G. We found that the homodimeric CaSR of each complex couples to a single G protein through a common mode. This involves the C-terminal helix of each Gα subunit binding to a shallow pocket that is formed in one CaSR subunit by all three intracellular loops (ICL1-ICL3), an extended transmembrane helix 3 and an ordered C-terminal region. G-protein binding expands the transmembrane dimer interface, which is further stabilized by phospholipid. The restraint imposed by the receptor dimer, in combination with ICL2, enables G-protein activation by facilitating conformational transition of Gα. We identified a single Gα residue that determines G and G versus G selectivity. The length and flexibility of ICL2 allows CaSR to bind all three Gα subtypes, thereby conferring capacity for promiscuous G-protein coupling.

PubMed: 38632411
DOI: 10.1038/s41586-024-07331-1

Experimental method

ELECTRON MICROSCOPY (3.6 Å)