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Structure paper

TitlePromiscuous G-protein activation by the calcium-sensing receptor.
Journal, issue, pagesNature, Vol. 629, Issue 8011, Page 481-488, Year 2024
Publish dateApr 17, 2024
AuthorsHao Zuo / Jinseo Park / Aurel Frangaj / Jianxiang Ye / Guanqi Lu / Jamie J Manning / Wesley B Asher / Zhengyuan Lu / Guo-Bin Hu / Liguo Wang / Joshua Mendez / Edward Eng / Zhening Zhang / Xin Lin / Robert Grassucci / Wayne A Hendrickson / Oliver B Clarke / Jonathan A Javitch / Arthur D Conigrave / Qing R Fan /
PubMed AbstractThe 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 ...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.
External linksNature / PubMed:38632411
MethodsEM (single particle)
Resolution2.9 - 4.0 Å
Structure data

43811

9asb

EMDB-43811, PDB-9asb:
Structure of human calcium-sensing receptor in complex with chimeric Gq (miniGisq) protein in nanodiscs
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-43836: Consensus map of human CaSR-miniGisq complex in nanodiscs
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-43837: Local refinement map of CaSR extracellular domain in nanodisc-reconstituted human CaSR-miniGisq complex
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-43840: Local refinement map of CaSR transmembrane domain in nanodisc-reconstituted human CaSR-miniGisq complex
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-43841: Local refinement map of G protein in nanodisc-reconstituted human CaSR-miniGisq complex
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-43897: Consensus map of human CaSR-miniGis complex in nanodiscs
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-43898: Local refinement map of CaSR extracellular domain in nanodisc-reconstituted human CaSR-miniGis complex
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-43899: Local refinement map of CaSR transmembrane domain in nanodisc-reconstituted human CaSR-miniGis complex
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-43900: Local refinement map of G protein in nanodisc-reconstituted human CaSR-miniGis complex
Method: EM (single particle) / Resolution: 4.0 Å

43901

9avg

EMDB-43901, PDB-9avg:
Structure of human calcium-sensing receptor in complex with chimeric Gs (miniGis) protein in nanodiscs
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-43904: Consensus map of human CaSR-Gi3 complex in nanodiscs
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-43905: Local refinement map of CaSR extracellular domain in nanodisc-reconstituted human CaSR-Gi3 complex
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-43906: Local refinement map of CaSR transmembrane domain in nanodisc-reconstituted human CaSR-Gi3 complex
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-43907: Local refinement map of G protein in nanodisc-reconstituted human CaSR-Gi3 complex
Method: EM (single particle) / Resolution: 3.3 Å

43908

9avl

EMDB-43908, PDB-9avl:
Structure of human calcium-sensing receptor in complex with Gi3 protein in nanodiscs
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-43961: Consensus map of human CaSR-miniGisq complex in detergent
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-43962: Local refinement map of CaSR extracellular domain (ECD) in detergent-solubilized human CaSR-miniGisq complex
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-43963: Local refinement map of CaSR transmembrane domain (TMD) in detergent-solubilized human CaSR-miniGisq complex
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-43964: Local refinement map of G protein in detergent-solubilized human CaSR-miniGisq complex
Method: EM (single particle) / Resolution: 3.1 Å

43966

9axf

EMDB-43966, PDB-9axf:
Structure of human calcium-sensing receptor in complex with chimeric Gq (miniGisq) protein in detergent
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-43986: Consensus map of human CaSR-miniGi1 complex in detergent
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-43987: Local refinement map of CaSR extracellular domain (ECD) in detergent-solubilized human CaSR-miniGi1 complex
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-43988: Local refinement map of CaSR transmembrane domain (TMD) in detergent-solubilized human CaSR-miniGi1 complex
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-43989: Local refinement map of G protein in detergent-solubilized human CaSR-miniGi1 complex
Method: EM (single particle) / Resolution: 3.2 Å

43990

9ayf

EMDB-43990, PDB-9ayf:
Structure of human calcium-sensing receptor in complex with Gi1 (miniGi1) protein in detergent
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-TCR:
CYCLOMETHYLTRYPTOPHAN

ChemComp-PO4:
PHOSPHATE ION / Phosphate

ChemComp-CA:
Unknown entry

ChemComp-9IG:
3-(2-chlorophenyl)-N-[(1R)-1-(3-methoxyphenyl)ethyl]propan-1-amine

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

PDB-1af7:
CHER FROM SALMONELLA TYPHIMURIUM

ChemComp-AV0:
Lauryl Maltose Neopentyl Glycol

ChemComp-CLR:
CHOLESTEROL / Cholesterol

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • lama glama (llama)
KeywordsMEMBRANE PROTEIN / Calcium-sensing receptor / G-protein-coupled receptor / G protein / signal transduction

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