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Yorodumi- PDB-9avg: Structure of human calcium-sensing receptor in complex with chime... -
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-Basic information
Entry | Database: PDB / ID: 9avg | ||||||
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Title | Structure of human calcium-sensing receptor in complex with chimeric Gs (miniGis) protein in nanodiscs | ||||||
Components |
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Keywords | MEMBRANE PROTEIN / Calcium-sensing receptor / G-protein-coupled receptor / G protein / signal transduction | ||||||
Function / homology | Function and homology information bile acid secretion / chemosensory behavior / cellular response to peptide / response to fibroblast growth factor / sensory perception of chemical stimulus / cellular response to vitamin D / phosphatidylinositol phospholipase C activity / Class C/3 (Metabotropic glutamate/pheromone receptors) / calcium ion import / positive regulation of positive chemotaxis ...bile acid secretion / chemosensory behavior / cellular response to peptide / response to fibroblast growth factor / sensory perception of chemical stimulus / cellular response to vitamin D / phosphatidylinositol phospholipase C activity / Class C/3 (Metabotropic glutamate/pheromone receptors) / calcium ion import / positive regulation of positive chemotaxis / fat pad development / 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 / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / D1 dopamine receptor binding / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / anatomical structure morphogenesis / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / beta-2 adrenergic receptor binding / axon terminus / JNK cascade / regulation of mitotic spindle organization / cellular response to forskolin / positive regulation of vasoconstriction / chloride transmembrane transport / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / ossification / Regulation of insulin secretion / response to ischemia / G protein-coupled receptor binding / G protein-coupled receptor activity / cellular response to glucose stimulus / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / 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 / G-protein activation / 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 / response to peptide hormone / 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 / 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 / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / cellular response to hypoxia / G alpha (s) signalling events / G alpha (q) signalling events Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å | ||||||
Authors | Zuo, H. / Park, J. / Frangaj, A. / Ye, J. / Lu, G. / Manning, J.J. / Asher, W.B. / Lu, Z. / Hu, G. / Wang, L. ...Zuo, H. / Park, J. / Frangaj, A. / Ye, J. / Lu, G. / Manning, J.J. / Asher, W.B. / Lu, Z. / Hu, G. / Wang, L. / Mendez, J. / Eng, E. / Zhang, Z. / Lin, X. / Grasucci, R. / Hendrickson, W.A. / Clarke, O.B. / Javitch, J.A. / Conigrave, A.D. / Fan, Q.R. | ||||||
Funding support | United States, 1items
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Citation | Journal: Nature / Year: 2024 Title: Promiscuous G-protein activation by the calcium-sensing receptor. Authors: Hao 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 / ...Authors: Hao 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 / Abstract: 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 ...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. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 9avg.cif.gz | 412.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb9avg.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 9avg.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 9avg_validation.pdf.gz | 1.1 MB | Display | wwPDB validaton report |
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Full document | 9avg_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | 9avg_validation.xml.gz | 65.5 KB | Display | |
Data in CIF | 9avg_validation.cif.gz | 97.3 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/av/9avg ftp://data.pdbj.org/pub/pdb/validation_reports/av/9avg | HTTPS FTP |
-Related structure data
Related structure data | 43901MC 9asbC 9avlC 9axfC 9ayfC C: citing same article (ref.) M: map data used to model this data |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 2 types, 3 molecules QRA
#1: Protein | Mass: 102864.617 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Details: The CaSR construct consists of residues 1-903 and a Flag tag inserted after the signal peptide. Source: (gene. exp.) Homo sapiens (human) / Gene: CASR, GPRC2A, PCAR1 / Cell line (production host): HEK293 GnTI- / Production host: Homo sapiens (human) / References: UniProt: P41180 #2: Protein | | Mass: 28430.295 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Details: Chimeric miniG(i)(s) alpha construct was designed where the N-terminal 25 amino acids of G(s) alpha was replaced with the initial 18 residues of G(i1) alpha Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1, GNAS / Cell line (production host): HEK293 GnTI- / Production host: Homo sapiens (human) / References: UniProt: P63096, UniProt: A0A590UJY2 |
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-Guanine nucleotide-binding protein ... , 2 types, 2 molecules BG
#3: Protein | Mass: 38413.895 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Details: The guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 construct contains a Flag epitope fused to the N-terminus. Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Cell line (production host): HEK293 GnTI- / Production host: Homo sapiens (human) / References: UniProt: P62873 |
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#4: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Cell line (production host): HEK293 GnTI- / Production host: Homo sapiens (human) / References: UniProt: P59768 |
-Sugars , 2 types, 9 molecules
#5: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source #6: Sugar | ChemComp-NAG / |
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-Non-polymers , 6 types, 14 molecules
#7: Chemical | #8: Chemical | #9: Chemical | ChemComp-CA / #10: Chemical | #11: Chemical | ChemComp-Y01 / | #12: Chemical | ChemComp-A1AF7 / ( | Mass: 749.007 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C40H77O10P |
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-Details
Has ligand of interest | N |
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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 |
-Sample preparation
Component | Name: Human CaSR in complex with chimeric Gs (miniGis) protein Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT | |||||||||||||||||||||||||||||||||||
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Molecular weight | Value: 0.276 MDa / Experimental value: NO | |||||||||||||||||||||||||||||||||||
Source (natural) | Organism: Homo sapiens (human) | |||||||||||||||||||||||||||||||||||
Source (recombinant) | Organism: Homo sapiens (human) / Cell: HEK293 GnTI- | |||||||||||||||||||||||||||||||||||
Buffer solution | pH: 7.5 | |||||||||||||||||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 3.9 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | |||||||||||||||||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R0.6/1 | |||||||||||||||||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K Details: The sample was blotted for 6s before plunge-frozen. |
-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: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 1900 nm / Nominal defocus min: 1100 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 100 K |
Image recording | Average exposure time: 2.72 sec. / Electron dose: 67.9 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 29091 |
EM imaging optics | Energyfilter name: GIF Bioquantum / Energyfilter slit width: 15 eV |
Image scans | Width: 11520 / Height: 8184 |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 4867087 | ||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 45862 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||
Atomic model building | Protocol: FLEXIBLE FIT / Space: REAL | ||||||||||||||||||||||||||||||||||||
Atomic model building | 3D fitting-ID: 1 / Source name: PDB / Type: experimental model
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