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- PDB-7e6t: Structural insights into the activation of human calcium-sensing ... -

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Basic information

Entry
Database: PDB / ID: 7e6t
TitleStructural insights into the activation of human calcium-sensing receptor
ComponentsExtracellular calcium-sensing receptor
KeywordsSTRUCTURAL PROTEIN / G-protein-coupled receptor (GPCR) / Calcium-sensing receptor (CaSR) / cryo-electron microscopy (cryo-EM) / calcium ions / nanobody
Function / homology
Function and homology information


regulation of presynaptic membrane potential / bile acid secretion / chemosensory behavior / response to fibroblast growth factor / cellular response to peptide / cellular response to vitamin D / phosphatidylinositol-4,5-bisphosphate phospholipase C activity / Class C/3 (Metabotropic glutamate/pheromone receptors) / calcium ion import / positive regulation of positive chemotaxis ...regulation of presynaptic membrane potential / bile acid secretion / chemosensory behavior / response to fibroblast growth factor / cellular response to peptide / cellular response to vitamin D / phosphatidylinositol-4,5-bisphosphate phospholipase C activity / Class C/3 (Metabotropic glutamate/pheromone receptors) / calcium ion import / positive regulation of positive chemotaxis / fat pad development / cellular response to hepatocyte growth factor stimulus / amino acid binding / branching morphogenesis of an epithelial tube / positive regulation of calcium ion import / positive regulation of vasoconstriction / regulation of calcium ion transport / cellular response to low-density lipoprotein particle stimulus / anatomical structure morphogenesis / detection of calcium ion / JNK cascade / axon terminus / ossification / chloride transmembrane transport / response to ischemia / cellular response to glucose stimulus / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / vasodilation / integrin binding / intracellular calcium ion homeostasis / presynaptic membrane / G alpha (i) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / basolateral plasma membrane / G alpha (q) signalling events / cellular response to hypoxia / transmembrane transporter binding / positive regulation of ERK1 and ERK2 cascade / apical plasma membrane / G protein-coupled receptor signaling pathway / neuronal cell body / positive regulation of cell population proliferation / calcium ion binding / positive regulation of gene expression / protein kinase binding / glutamatergic synapse / cell surface / protein homodimerization activity / identical protein binding / plasma membrane
Similarity search - Function
GPCR, family 3, extracellular calcium-sensing receptor-related / G-protein coupled receptors family 3 signature 1. / G-protein coupled receptors family 3 signature 3. / 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 / GPCR, family 3 / G-protein coupled receptors family 3 profile. ...GPCR, family 3, extracellular calcium-sensing receptor-related / G-protein coupled receptors family 3 signature 1. / G-protein coupled receptors family 3 signature 3. / 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 / 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 / Periplasmic binding protein-like I
Similarity search - Domain/homology
PHOSPHATE ION / CYCLOMETHYLTRYPTOPHAN / Extracellular calcium-sensing receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsGeng, Y. / Chen, X.C. / Wang, L. / Cui, Q.Q. / Ding, Z.Y. / Han, L. / Kou, Y.J. / Zhang, W.Q. / Wang, H.N. / Jia, X.M. ...Geng, Y. / Chen, X.C. / Wang, L. / Cui, Q.Q. / Ding, Z.Y. / Han, L. / Kou, Y.J. / Zhang, W.Q. / Wang, H.N. / Jia, X.M. / Dai, M. / Shi, Z.Z. / Li, Y.Y. / Li, X.Y.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)No. 31670743 China
Chinese Academy of Sciences2015123456005 China
CitationJournal: Elife / Year: 2021
Title: Structural insights into the activation of human calcium-sensing receptor.
Authors: Xiaochen Chen / Lu Wang / Qianqian Cui / Zhanyu Ding / Li Han / Yongjun Kou / Wenqing Zhang / Haonan Wang / Xiaomin Jia / Mei Dai / Zhenzhong Shi / Yuying Li / Xiyang Li / Yong Geng /
Abstract: Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that maintains Ca homeostasis in serum. Here, we present the cryo-electron microscopy structures of the CaSR in the inactive and ...Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that maintains Ca homeostasis in serum. Here, we present the cryo-electron microscopy structures of the CaSR in the inactive and agonist+PAM bound states. Complemented with previously reported structures of CaSR, we show that in addition to the full inactive and active states, there are multiple intermediate states during the activation of CaSR. We used a negative allosteric nanobody to stabilize the CaSR in the fully inactive state and found a new binding site for Ca ion that acts as a composite agonist with L-amino acid to stabilize the closure of active Venus flytraps. Our data show that agonist binding leads to compaction of the dimer, proximity of the cysteine-rich domains, large-scale transitions of seven-transmembrane domains, and inter- and intrasubunit conformational changes of seven-transmembrane domains to accommodate downstream transducers. Our results reveal the structural basis for activation mechanisms of CaSR and clarify the mode of action of Ca ions and L-amino acid leading to the activation of the receptor.
History
DepositionFeb 24, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 22, 2021Provider: repository / Type: Initial release
Revision 1.0Sep 22, 2021Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Sep 22, 2021Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Sep 22, 2021Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Sep 22, 2021Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Sep 22, 2021Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Jul 2, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

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Assembly

Deposited unit
B: Extracellular calcium-sensing receptor
A: Extracellular calcium-sensing receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)196,40016
Polymers194,6522
Non-polymers1,74814
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area9190 Å2
ΔGint-99 kcal/mol
Surface area80140 Å2
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11B
21A

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010B1 - 868
2010A1 - 868

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Components

#1: Protein Extracellular calcium-sensing receptor / CaR / CaSR / hCasR / Parathyroid cell calcium-sensing receptor 1 / PCaR1


Mass: 97326.094 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASR, GPRC2A, PCAR1 / Production host: Homo sapiens (human) / References: UniProt: P41180
#2: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#4: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#5: Chemical ChemComp-TCR / CYCLOMETHYLTRYPTOPHAN


Type: L-peptide linking / Mass: 216.236 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H12N2O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: 2D ARRAY / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: CaSR, TNCA, Ca, PO4 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: NITROGEN

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Alignment procedure: ZEMLIN TABLEAU
Specimen holderCryogen: NITROGEN / Specimen holder model: SIDE ENTRY, EUCENTRIC
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsPhase plate: ZERNIKE PHASE PLATE

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 248900 / Symmetry type: POINT
RefinementResolution: 3→353.6 Å / Cor.coef. Fo:Fc: 0.672 / SU B: 8.559 / SU ML: 0.117 / ESU R: 0.093
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
RfactorNum. reflection% reflection
Rwork0.50501 --
obs0.50501 3429329 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 179.014 Å2
Baniso -1Baniso -2Baniso -3
1-0.56 Å2-0.5 Å20.03 Å2
2--0.49 Å2-0.03 Å2
3----1.05 Å2
Refinement stepCycle: 1 / Total: 12766
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00213062
ELECTRON MICROSCOPYf_angle_d0.45417727
ELECTRON MICROSCOPYf_dihedral_angle_d21.6821728
ELECTRON MICROSCOPYf_chiral_restr0.041984
ELECTRON MICROSCOPYf_plane_restr0.0032244
Refine LS restraints NCS

Ens-ID: 1 / Number: 43116 / Refine-ID: ELECTRON MICROSCOPY / Type: interatomic distance / Rms dev position: 0.21 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1B
2A
LS refinement shellResolution: 3→3.078 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork3.573 253709 -
obs--100 %

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