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TitleAllosteric modulation and G-protein selectivity of the Ca-sensing receptor.
Journal, issue, pagesNature, Vol. 626, Issue 8001, Page 1141-1148, Year 2024
Publish dateFeb 7, 2024
AuthorsFeng He / Cheng-Guo Wu / Yang Gao / Sabrina N Rahman / Magda Zaoralová / Makaía M Papasergi-Scott / Ting-Jia Gu / Michael J Robertson / Alpay B Seven / Lingjun Li / Jesper M Mathiesen / Georgios Skiniotis /
PubMed AbstractThe calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor (GPCR) that has a central role in regulating systemic calcium homeostasis. Here we use cryo-electron microscopy and ...The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor (GPCR) that has a central role in regulating systemic calcium homeostasis. Here we use cryo-electron microscopy and functional assays to investigate the activation of human CaSR embedded in lipid nanodiscs and its coupling to functional G versus G proteins in the presence and absence of the calcimimetic drug cinacalcet. High-resolution structures show that both G and G drive additional conformational changes in the activated CaSR dimer to stabilize a more extensive asymmetric interface of the seven-transmembrane domain (7TM) that involves key protein-lipid interactions. Selective G and G coupling by the receptor is achieved through substantial rearrangements of intracellular loop 2 and the C terminus, which contribute differentially towards the binding of the two G-protein subtypes, resulting in distinct CaSR-G-protein interfaces. The structures also reveal that natural polyamines target multiple sites on CaSR to enhance receptor activation by zipping negatively charged regions between two protomers. Furthermore, we find that the amino acid L-tryptophan, a well-known ligand of CaSR extracellular domains, occupies the 7TM bundle of the G-protein-coupled protomer at the same location as cinacalcet and other allosteric modulators. Together, these results provide a framework for G-protein activation and selectivity by CaSR, as well as its allosteric modulation by endogenous and exogenous ligands.
External linksNature / PubMed:38326620
MethodsEM (single particle)
Resolution2.6 - 3.9 Å
Structure data

40914

8szf

EMDB-40914, PDB-8szf:
Cryo-EM structure of cinacalcet-bound active-state human calcium-sensing receptor CaSR in lipid nanodiscs
Method: EM (single particle) / Resolution: 2.8 Å

40915

8szg

EMDB-40915, PDB-8szg:
Cryo-EM structure of cinacalcet-bound human calcium-sensing receptor CaSR-Gq complex in lipid nanodiscs
Method: EM (single particle) / Resolution: 3.6 Å

40916

8szh

EMDB-40916, PDB-8szh:
Cryo-EM structure of cinacalcet-bound human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs
Method: EM (single particle) / Resolution: 3.1 Å

40917

8szi

EMDB-40917, PDB-8szi:
Cryo-EM structure of PAM-free human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-41908: Local refinement map on VFT-CRD of active-state CaSR in lipid nanodiscs
Method: EM (single particle) / Resolution: 2.6 Å

EMDB-41909: Consensus refinement map of active-state human CaSR in lipid nanodiscs
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-41910: Local refinement map on CRD-7TM of active-state CaSR in lipid nanodiscs
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-41925: Local refinement map on VFT-CRD of cinacalcet-bound human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-41926: Local refinement map on Gi of cinacalcet-bound human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-41927: Local refinement map on CRD-7TM of cinacalcet-bound human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-41928: Consensus refinement map of cinacalcet-bound human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-41949: Consensus refinement map of cinacalcet-bound human calcium-sensing receptor CaSR-Gq complex in lipid nanodiscs
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-41950: Local refinement map on CRD-7TM of cinacalcet-bound human calcium-sensing receptor CaSR-Gq complex in lipid nanodiscs
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-41951: Local refinement map on VFT-CRD of cinacalcet-bound human calcium-sensing receptor CaSR-Gq complex in lipid nanodiscs
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-41952: Local refinement map on Gq of cinacalcet-bound human calcium-sensing receptor CaSR-Gq complex in lipid nanodiscs
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-41953: Consensus refinement map of PAM-free human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-41954: Local refinement map on VFT-CRD of PAM-free human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-41956: Local refinement map on CRD-7TM of PAM-free human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-41957: Local refinement map on Gi of PAM-free human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs
Method: EM (single particle) / Resolution: 3.5 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-TRP:
TRYPTOPHAN

ChemComp-CA:
Unknown entry

ChemComp-PO4:
PHOSPHATE ION

ChemComp-YP4:
N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine / medication*YM

ChemComp-SPM:
SPERMINE

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

ChemComp-CLR:
CHOLESTEROL

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / Family C GPCR / Calcium-sensing Receptor (CaSR) / Lipid Nanodiscs / Positive Allosteric Modulator / Membrane Protein / Heterotrimeric G protein / Cryo-EM

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