Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Allosteric modulation and G-protein selectivity of the Ca-sensing receptor.
Journal, issue, pages	Nature, Vol. 626, Issue 8001, Page 1141-1148, Year 2024
Publish date	Feb 7, 2024
Authors	Feng 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 Abstract	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 ...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 links	Nature / PubMed:38326620
Methods	EM (single particle)
Resolution	2.8 - 3.6 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
Chemicals	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine ChemComp-TRP: TRYPTOPHAN / Tryptophan ChemComp-CA: Unknown entry ChemComp-PO4: PHOSPHATE ION / Phosphate ChemComp-YP4: N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine / medicationYM / Cinacalcet ChemComp-SPM: SPERMINE / Spermine ChemComp-PCW: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipidYM ChemComp-CLR: CHOLESTEROL / Cholesterol ChemComp-HOH: WATER / Water
Source	homo sapiens (human)
Keywords	SIGNALING PROTEIN / Family C GPCR / Calcium-sensing Receptor (CaSR) / Lipid Nanodiscs / Positive Allosteric Modulator / Membrane Protein / Heterotrimeric G protein / Cryo-EM