PDB-8szg: Cryo-EM structure of cinacalcet-bound human calcium-sensing recep...

Basic information

• Entry: Database: PDB / ID: 8szg
• Title: Cryo-EM structure of cinacalcet-bound human calcium-sensing receptor CaSR-Gq complex in lipid nanodiscs

Components

• (Extracellular calcium-sensing ...) x 2
• (Guanine nucleotide-binding protein ...) x 3

• Keywords: SIGNALING PROTEIN / Family C GPCR / Calcium-sensing Receptor (CaSR) / Heterotrimeric G protein / Cryo-EM / Lipid Nanodiscs / Positive Allosteric Modulator / Membrane Protein

Function / homology

Function:

bile acid secretion / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / chemosensory behavior / cellular response to peptide / response to fibroblast growth factor / PLC beta mediated events / phospholipase C-activating dopamine receptor signaling pathway / regulation of platelet activation / cellular response to vitamin D / phosphatidylinositol phospholipase C activity / phototransduction, visible light / entrainment of circadian clock / Class C/3 (Metabotropic glutamate/pheromone receptors) / calcium ion import / glutamate receptor signaling pathway / regulation of canonical Wnt signaling pathway / positive regulation of positive chemotaxis / fat pad development / action potential / amino acid binding / cellular response to hepatocyte growth factor stimulus / branching morphogenesis of an epithelial tube / positive regulation of calcium ion import / regulation of calcium ion transport / : / cellular response to low-density lipoprotein particle stimulus / detection of calcium ion / photoreceptor outer segment / anatomical structure morphogenesis / axon terminus / JNK cascade / positive regulation of vasoconstriction / chloride transmembrane transport / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / ossification / GTPase activator activity / response to ischemia / G protein-coupled receptor activity / G protein-coupled receptor binding / cellular response to glucose stimulus / negative regulation of protein kinase activity / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G-protein activation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / intracellular calcium ion homeostasis / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / vasodilation / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / blood coagulation / signaling receptor complex adaptor activity / integrin binding / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / G alpha (i) signalling events / fibroblast proliferation / cellular response to hypoxia / G alpha (s) signalling events / G alpha (q) signalling events / basolateral plasma membrane / nuclear membrane / transmembrane transporter binding / cell population proliferation

Domain/homology:

GPCR, family 3, extracellular calcium-sensing receptor-related / G-protein alpha subunit, group Q / G-protein coupled receptors family 3 signature 1. / G-protein coupled receptors family 3 signature 2. / GPCR, family 3, nine cysteines domain / GPCR, family 3, nine cysteines domain superfamily / Nine Cysteines Domain of family 3 GPCR / GPCR, family 3, conserved site / G-protein coupled receptors family 3 signature 3. / GPCR, family 3 / G-protein coupled receptors family 3 profile. / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / Receptor, ligand binding region / Receptor family ligand binding region / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / Periplasmic binding protein-like I / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase

Component:

CHOLESTEROL / 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / PHOSPHATE ION / SPERMINE / TRYPTOPHAN / Chem-YP4 / Extracellular calcium-sensing receptor / Guanine nucleotide-binding protein G(q) subunit alpha / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

• Biological species: Homo sapiens (human)
• Method: ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
• Authors: He, F. / Wu, C. / Gao, Y. / Skiniotis, G.

Funding support

United States, 1items

Organization	Grant number	Country
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)	5R01DK132902-02	United States

• Citation: Journal: Nature / Year: 2024; Title: Allosteric modulation and G-protein selectivity of the Ca-sensing receptor.; 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 / ; 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 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.

History

Deposition	May 29, 2023	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Feb 7, 2024	Provider: repository / Type: Initial release
Revision 1.1	Feb 21, 2024	Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2	Mar 13, 2024	Group: Database references / Category: citation Item: _citation.journal_volume / _citation.page_first / _citation.page_last