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- PDB-8szh: Cryo-EM structure of cinacalcet-bound human calcium-sensing recep... -
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Basic information
Entry | Database: PDB / ID: 8szh | ||||||
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Title | Cryo-EM structure of cinacalcet-bound human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs | ||||||
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![]() | SIGNALING PROTEIN / Family C GPCR / Calcium-sensing Receptor (CaSR) / Heterotrimeric G protein / Cryo-EM / Lipid Nanodiscs / Positive Allosteric Modulator / Membrane Protein | ||||||
Function / homology | ![]() bile acid secretion / chemosensory behavior / cellular response to peptide / response to fibroblast growth factor / cellular response to vitamin D / phosphatidylinositol phospholipase C activity / negative regulation of adenylate cyclase activity / Class C/3 (Metabotropic glutamate/pheromone receptors) / calcium ion import / GTP metabolic process ...bile acid secretion / chemosensory behavior / cellular response to peptide / response to fibroblast growth factor / cellular response to vitamin D / phosphatidylinositol phospholipase C activity / negative regulation of adenylate cyclase activity / Class C/3 (Metabotropic glutamate/pheromone receptors) / calcium ion import / GTP metabolic process / positive regulation of positive chemotaxis / fat pad development / G protein-coupled dopamine receptor signaling pathway / 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 / positive regulation of macroautophagy / cellular response to low-density lipoprotein particle stimulus / detection of calcium ion / Adenylate cyclase inhibitory pathway / anatomical structure morphogenesis / axon terminus / JNK cascade / positive regulation of vasoconstriction / chloride transmembrane transport / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / ossification / response to ischemia / G protein-coupled receptor binding / G protein-coupled receptor activity / cellular response to glucose stimulus / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / positive regulation of insulin secretion / G-protein activation / 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 / vasodilation / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / 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 / 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 / midbody / G alpha (i) signalling events / fibroblast proliferation / cellular response to hypoxia / G alpha (s) signalling events / G alpha (q) signalling events / basolateral plasma membrane / transmembrane transporter binding / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / positive regulation of ERK1 and ERK2 cascade / G protein-coupled receptor signaling pathway / cell cycle / apical plasma membrane / cell division / lysosomal membrane / GTPase activity Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å | ||||||
![]() | He, F. / Wu, C. / Gao, Y. / Skiniotis, G. | ||||||
Funding support | ![]()
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![]() | ![]() 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 ...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 |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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PDBx/mmCIF format | ![]() | 468.7 KB | Display | ![]() |
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PDB format | ![]() | 368.7 KB | Display | ![]() |
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-Validation report
Summary document | ![]() | 1.5 MB | Display | ![]() |
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Full document | ![]() | 1.5 MB | Display | |
Data in XML | ![]() | 65.2 KB | Display | |
Data in CIF | ![]() | 97.4 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 40916MC ![]() 8szfC ![]() 8szgC ![]() 8sziC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Protein , 1 types, 2 molecules AB
#1: Protein | Mass: 99929.133 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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-Guanine nucleotide-binding protein ... , 3 types, 3 molecules CDE
#2: Protein | Mass: 40585.137 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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#3: Protein | Mass: 37573.988 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
#4: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
-Sugars , 2 types, 6 molecules ![](data/chem/img/NAG.gif)
#5: Polysaccharide | Source method: isolated from a genetically manipulated source #8: Sugar | |
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-Non-polymers , 8 types, 18 molecules ![](data/chem/img/YP4.gif)
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#6: Chemical | #7: Chemical | #9: Chemical | ChemComp-CA / #10: Chemical | #11: Chemical | #12: Chemical | ChemComp-SPM / #13: Chemical | ChemComp-CLR / | #14: Water | ChemComp-HOH / | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Cinacalcet-bound human calcium-sensing receptor CaSR-Gi complex in lipid nanodiscs Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT |
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Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() ![]() |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 500 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
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Processing
EM software | Name: PHENIX / Version: 1.20.1_4487: / Category: model refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 262847 / Symmetry type: POINT | ||||||||||||||||||||||||
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