[English] 日本語
Yorodumi
- PDB-7m3g: Asymmetric Activation of the Calcium Sensing Receptor Homodimer -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 7m3g
TitleAsymmetric Activation of the Calcium Sensing Receptor Homodimer
Components
  • Extracellular calcium-sensing receptor
  • etelcalcetide
KeywordsMEMBRANE PROTEIN / GPCR / calcium sensing receptor / active state / positive allosteric modulator / family C GPCR
Function / homology
Function and homology information


bile acid secretion / chemosensory behavior / response to fibroblast growth factor / cellular response to peptide / 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 / response to fibroblast growth factor / cellular response to peptide / 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 / cellular response to hepatocyte growth factor stimulus / amino acid binding / 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 / 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 activity / cellular response to glucose stimulus / positive regulation of insulin secretion / intracellular calcium ion homeostasis / vasodilation / integrin binding / phospholipase C-activating G protein-coupled receptor signaling pathway / cellular response to hypoxia / G alpha (i) signalling events / basolateral plasma membrane / G alpha (q) signalling events / 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 / 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 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 / Periplasmic binding protein-like I
Similarity search - Domain/homology
Chem-H43 / PHOSPHATE ION / TRYPTOPHAN / polypeptide(D) / Extracellular calcium-sensing receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsGao, Y. / Robertson, M.J. / Zhang, C. / Meyerowitz, J.G. / Panova, O. / Skiniotis, G.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS092695 United States
CitationJournal: Nature / Year: 2021
Title: Asymmetric activation of the calcium-sensing receptor homodimer.
Authors: Yang Gao / Michael J Robertson / Sabrina N Rahman / Alpay B Seven / Chensong Zhang / Justin G Meyerowitz / Ouliana Panova / Fadil M Hannan / Rajesh V Thakker / Hans Bräuner-Osborne / Jesper ...Authors: Yang Gao / Michael J Robertson / Sabrina N Rahman / Alpay B Seven / Chensong Zhang / Justin G Meyerowitz / Ouliana Panova / Fadil M Hannan / Rajesh V Thakker / Hans Bräuner-Osborne / Jesper M Mathiesen / Georgios Skiniotis /
Abstract: The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid ...The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders. CaSR is a family C G-protein-coupled receptor that functions as an obligate homodimer, with each protomer composed of a Ca-binding extracellular domain and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins. Here we present cryo-electron microscopy structures of near-full-length human CaSR in inactive or active states bound to Ca and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G-protein coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic drug locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this receptor.
History
DepositionMar 18, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 30, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 14, 2021Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jul 21, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Nov 20, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

-
Structure visualization

Movie
  • Deposited structure unit
  • Imaged by Jmol
  • Download
  • Superimposition on EM map
  • EMDB-23654
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

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


Theoretical massNumber of molelcules
Total (without water)210,05924
Polymers205,3234
Non-polymers4,73620
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

-
Components

-
Protein / Polypeptide(D) , 2 types, 4 molecules ABCD

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


Mass: 101745.445 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: 1-16 is signaling sequence, 17-24 is FLAG epitope tag, 25-27 is an 3-alanine linker, the receptor sequence starts at residue Y28 that should be re-numbered to 20, and ends at V902 that ...Details: 1-16 is signaling sequence, 17-24 is FLAG epitope tag, 25-27 is an 3-alanine linker, the receptor sequence starts at residue Y28 that should be re-numbered to 20, and ends at V902 that should be re-numbered to 894.
Source: (gene. exp.) Homo sapiens (human) / Gene: CASR, GPRC2A, PCAR1 / Cell (production host): sf9 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P41180
#2: Polypeptide(D) etelcalcetide


Mass: 916.134 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

-
Sugars , 2 types, 10 molecules

#3: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#5: 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.: 5 / Source method: obtained synthetically / Formula: C8H15NO6
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

-
Non-polymers , 4 types, 10 molecules

#4: Chemical ChemComp-H43 / 2-[4-[(3S)-3-[[(1R)-1-naphthalen-1-ylethyl]amino]pyrrolidin-1-yl]phenyl]ethanoic acid / Evocalcet


Mass: 374.475 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H26N2O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: agonist*YM
#6: Chemical ChemComp-TRP / TRYPTOPHAN


Type: L-peptide linking / Mass: 204.225 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H12N2O2
#7: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#8: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4

-
Details

Has ligand of interestY
Has protein modificationY

-
Experimental details

-
Experiment

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

-
Sample preparation

ComponentName: active-state human extracellular calcium-sensing receptor complexed with positive allosteric modulators etelcalcetide and evocalcet
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 200 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm) / Cell: sf9
Buffer solutionpH: 7.5
SpecimenConc.: 7 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

-
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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / C2 aperture diameter: 70 µm
Image recordingElectron dose: 64.9 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

-
Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM software
IDNameCategory
2SerialEMimage acquisition
13SerialEM3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 482939 / Symmetry type: POINT
RefinementHighest resolution: 2.5 Å
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00613623
ELECTRON MICROSCOPYf_angle_d0.94718482
ELECTRON MICROSCOPYf_dihedral_angle_d13.3751895
ELECTRON MICROSCOPYf_chiral_restr0.0572095
ELECTRON MICROSCOPYf_plane_restr0.0082322

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more