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- PDB-7e6u: the complex of inactive CaSR and NB2D11 -

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Basic information

Entry
Database: PDB / ID: 7e6u
Titlethe complex of inactive CaSR and NB2D11
Components
  • Extracellular calcium-sensing receptor
  • NB-2D11
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


bile acid secretion / chemosensory behavior / cellular response to peptide / response to fibroblast growth factor / 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 ...bile acid secretion / chemosensory behavior / cellular response to peptide / response to fibroblast growth factor / 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 / anatomical structure morphogenesis / axon terminus / positive regulation of vasoconstriction / JNK cascade / chloride transmembrane transport / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / ossification / G protein-coupled receptor activity / response to ischemia / cellular response to glucose stimulus / intracellular calcium ion homeostasis / positive regulation of insulin secretion / vasodilation / integrin binding / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / cellular response to hypoxia / G alpha (q) signalling events / basolateral plasma membrane / transmembrane transporter binding / positive regulation of ERK1 and ERK2 cascade / G protein-coupled receptor signaling pathway / apical plasma membrane / neuronal cell body / calcium ion binding / positive regulation of cell population proliferation / positive regulation of gene expression / protein kinase binding / 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 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 / GPCR family 3, C-terminal ...GPCR, family 3, extracellular calcium-sensing receptor-related / 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 / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / G-protein coupled receptors family 3 profile. / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I
Similarity search - Domain/homology
Extracellular calcium-sensing receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia phage EcSzw-2 (virus)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6 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)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

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Assembly

Deposited unit
A: Extracellular calcium-sensing receptor
D: NB-2D11
C: Extracellular calcium-sensing receptor
B: NB-2D11


Theoretical massNumber of molelcules
Total (without water)226,2054
Polymers226,2054
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area5370 Å2
ΔGint-22 kcal/mol
Surface area97110 Å2

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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: Antibody NB-2D11


Mass: 15776.344 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia phage EcSzw-2 (virus) / Production host: Escherichia phage EcSzw-2 (virus)

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: CaSR / Type: COMPLEX / Entity ID: all / 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 FIELDBright-field microscopy
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1215058 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00314589
ELECTRON MICROSCOPYf_angle_d0.81319774
ELECTRON MICROSCOPYf_dihedral_angle_d21.741920
ELECTRON MICROSCOPYf_chiral_restr0.0492173
ELECTRON MICROSCOPYf_plane_restr0.0042516

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