[English] 日本語
Yorodumi
- EMDB-40914: Cryo-EM structure of cinacalcet-bound active-state human calcium-... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-40914
TitleCryo-EM structure of cinacalcet-bound active-state human calcium-sensing receptor CaSR in lipid nanodiscs
Map data
Sample
  • Complex: Cinacalcet-bound active-state human calcium-sensing receptor CaSR dimer in lipid nanodiscs
    • Protein or peptide: Extracellular calcium-sensing receptor
    • Protein or peptide: Extracellular calcium-sensing receptor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: TRYPTOPHAN
  • Ligand: CALCIUM ION
  • Ligand: PHOSPHATE ION
  • Ligand: N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine
  • Ligand: SPERMINE
KeywordsFamily C GPCR / Calcium-sensing Receptor (CaSR) / Lipid Nanodiscs / Positive Allosteric Modulator / Membrane Protein / SIGNALING PROTEIN
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 / positive regulation of vasoconstriction / JNK cascade / 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 / positive regulation of cell population proliferation / calcium ion binding / 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
Extracellular calcium-sensing receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsHe F / Wu C / Gao Y / Skiniotis G
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)5R01DK132902-02 United States
CitationJournal: Nature / Year: 2024
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
DepositionMay 29, 2023-
Header (metadata) releaseFeb 7, 2024-
Map releaseFeb 7, 2024-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

-
Structure visualization

Supplemental images

emd_40914.png

Downloads & links

-
Map

FileDownload / File: emd_40914.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.87 Å/pix.
x 480 pix.
= 416.496 Å		0.87 Å/pix.
x 480 pix.
= 416.496 Å		0.87 Å/pix.
x 480 pix.
= 416.496 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8677 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-0.79950505 - 2.8957891
Average (Standard dev.)0.012926919 (±0.038791623)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 416.496 Å
α=β=γ: 90.0 °

-
Supplemental data

-
Additional map: Local unsharpened refinement map of CaSR VFT and CRD domains

Fileemd_40914_additional_1.map
AnnotationLocal unsharpened refinement map of CaSR VFT and CRD domains
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Additional map: Local unsharpened refinement map of CaSR CRD and 7TM domains

Fileemd_40914_additional_2.map
AnnotationLocal unsharpened refinement map of CaSR CRD and 7TM domains
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
Entire : Cinacalcet-bound active-state human calcium-sensing receptor CaSR...

EntireName: Cinacalcet-bound active-state human calcium-sensing receptor CaSR dimer in lipid nanodiscs
Components
  • Complex: Cinacalcet-bound active-state human calcium-sensing receptor CaSR dimer in lipid nanodiscs
    • Protein or peptide: Extracellular calcium-sensing receptor
    • Protein or peptide: Extracellular calcium-sensing receptor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: TRYPTOPHAN
  • Ligand: CALCIUM ION
  • Ligand: PHOSPHATE ION
  • Ligand: N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine
  • Ligand: SPERMINE

-
Supramolecule #1: Cinacalcet-bound active-state human calcium-sensing receptor CaSR...

SupramoleculeName: Cinacalcet-bound active-state human calcium-sensing receptor CaSR dimer in lipid nanodiscs
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

-
Macromolecule #1: Extracellular calcium-sensing receptor

MacromoleculeName: Extracellular calcium-sensing receptor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 123.820969 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DYKDDDDKAA AYGPDQRAQK KGDIILGGLF PIHFGVAAKD QDLKSRPESV ECIRYNFRGF RWLQAMIFAI EEINSSPALL PNLTLGYRI FDTCNTVSKA LEATLSFVAQ NKIDSLNLDE FCNCSEHIPS TIAVVGATGS GVSTAVANLL GLFYIPQVSY A SSSRLLSN ...String:
DYKDDDDKAA AYGPDQRAQK KGDIILGGLF PIHFGVAAKD QDLKSRPESV ECIRYNFRGF RWLQAMIFAI EEINSSPALL PNLTLGYRI FDTCNTVSKA LEATLSFVAQ NKIDSLNLDE FCNCSEHIPS TIAVVGATGS GVSTAVANLL GLFYIPQVSY A SSSRLLSN KNQFKSFLRT IPNDEHQATA MADIIEYFRW NWVGTIAADD DYGRPGIEKF REEAEERDIC IDFSELISQY SD EEEIQHV VEVIQNSTAK VIVVFSSGPD LEPLIKEIVR RNITGKIWLA SEAWASSSLI AMPQYFHVVG GTIGFALKAG QIP GFREFL KKVHPRKSVH NGFAKEFWEE TFNCHLQEGA KGPLPVDTFL RGHEESGDRF SNSSTAFRPL CTGDENISSV ETPY IDYTH LRISYNVYLA VYSIAHALQD IYTCLPGRGL FTNGSCADIK KVEAWQVLKH LRHLNFTNNM GEQVTFDECG DLVGN YSII NWHLSPEDGS IVFKEVGYYN VYAKKGERLF INEEKILWSG FSREVPFSNC SRDCLAGTRK GIIEGEPTCC FECVEC PDG EYSDETDASA CNKCPDDFWS NENHTSCIAK EIEFLSWTEP FGIALTLFAV LGIFLTAFVL GVFIKFRNTP IVKATNR EL SYLLLFSLLC CFSSSLFFIG EPQDWTCRLR QPAFGISFVL CISCILVKTN RVLLVFEAKI PTSFHRKWWG LNLQFLLV F LCTFMQIVIC VIWLYTAPPS SYRNQELEDE IIFITCHEGS LMALGFLIGY TCLLAAICFF FAFKSRKLPE NFNEAKFIT FSMLIFFIVW ISFIPAYAST YGKFVSAVEV IAILAASFGL LACIFFNKIY IILFKPSRNT IEEVRCSTAA HAFKVAARAT LRRSNVTST SVTSVNQAST SRLEGLQSEN HRLRMKITEL DKDLEEVTMQ LQDTPEKKTN SGGSVFTLED FVGDWEQTAA Y NLDQVLEQ GGVSSLLQNL AVSVTPIQRI VRSGENALKI DIHVIIPYEG LSADQMAQIE EVFKVVYPVD DHHFKVILPY GT LVIDGVT PNMLNYFGRP YEGIAVFDGK KITVTGTLWN GNKIIDERLI TPDGSMLFRV TINS

UniProtKB: Extracellular calcium-sensing receptor

-
Macromolecule #2: Extracellular calcium-sensing receptor

MacromoleculeName: Extracellular calcium-sensing receptor / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 108.023055 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: WSHPQFEKGG GSGGGSGGSA WSHPQFEKGS AAAYGPDQRA QKKGDIILGG LFPIHFGVAA KDQDLKSRPE SVECIRYNFR GFRWLQAMI FAIEEINSSP ALLPNLTLGY RIFDTCNTVS KALEATLSFV AQNKIDSLNL DEFCNCSEHI PSTIAVVGAT G SGVSTAVA ...String:
WSHPQFEKGG GSGGGSGGSA WSHPQFEKGS AAAYGPDQRA QKKGDIILGG LFPIHFGVAA KDQDLKSRPE SVECIRYNFR GFRWLQAMI FAIEEINSSP ALLPNLTLGY RIFDTCNTVS KALEATLSFV AQNKIDSLNL DEFCNCSEHI PSTIAVVGAT G SGVSTAVA NLLGLFYIPQ VSYASSSRLL SNKNQFKSFL RTIPNDEHQA TAMADIIEYF RWNWVGTIAA DDDYGRPGIE KF REEAEER DICIDFSELI SQYSDEEEIQ HVVEVIQNST AKVIVVFSSG PDLEPLIKEI VRRNITGKIW LASEAWASSS LIA MPQYFH VVGGTIGFAL KAGQIPGFRE FLKKVHPRKS VHNGFAKEFW EETFNCHLQE GAKGPLPVDT FLRGHEESGD RFSN SSTAF RPLCTGDENI SSVETPYIDY THLRISYNVY LAVYSIAHAL QDIYTCLPGR GLFTNGSCAD IKKVEAWQVL KHLRH LNFT NNMGEQVTFD ECGDLVGNYS IINWHLSPED GSIVFKEVGY YNVYAKKGER LFINEEKILW SGFSREVPFS NCSRDC LAG TRKGIIEGEP TCCFECVECP DGEYSDETDA SACNKCPDDF WSNENHTSCI AKEIEFLSWT EPFGIALTLF AVLGIFL TA FVLGVFIKFR NTPIVKATNR ELSYLLLFSL LCCFSSSLFF IGEPQDWTCR LRQPAFGISF VLCISCILVK TNRVLLVF E AKIPTSFHRK WWGLNLQFLL VFLCTFMQIV ICVIWLYTAP PSSYRNQELE DEIIFITCHE GSLMALGFLI GYTCLLAAI CFFFAFKSRK LPENFNEAKF ITFSMLIFFI VWISFIPAYA STYGKFVSAV EVIAILAASF GLLACIFFNK IYIILFKPSR NTIEEVRCS TAAHAFKVAA RATLRRSNVT GSSTNNNEEE KSRLLEKENR ELEKIIAEKE ERVSELRHQL QSRQQLKKTN

UniProtKB: Extracellular calcium-sensing receptor

-
Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

-
Macromolecule #5: TRYPTOPHAN

MacromoleculeName: TRYPTOPHAN / type: ligand / ID: 5 / Number of copies: 2 / Formula: TRP
Molecular weightTheoretical: 204.225 Da
Chemical component information

ChemComp-TRP:
TRYPTOPHAN

-
Macromolecule #6: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 6 / Number of copies: 4 / Formula: CA
Molecular weightTheoretical: 40.078 Da

-
Macromolecule #7: PHOSPHATE ION

MacromoleculeName: PHOSPHATE ION / type: ligand / ID: 7 / Number of copies: 2 / Formula: PO4
Molecular weightTheoretical: 94.971 Da
Chemical component information

ChemComp-PO4:
PHOSPHATE ION

-
Macromolecule #8: N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]pr...

MacromoleculeName: N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine
type: ligand / ID: 8 / Number of copies: 2 / Formula: YP4
Molecular weightTheoretical: 357.412 Da
Chemical component information

ChemComp-YP4:
N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine / medication*YM

-
Macromolecule #9: SPERMINE

MacromoleculeName: SPERMINE / type: ligand / ID: 9 / Number of copies: 1 / Formula: SPM
Molecular weightTheoretical: 202.34 Da
Chemical component information

ChemComp-SPM:
SPERMINE

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

Concentration7.00 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

-
Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

-
Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7m3f

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 234170
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

+
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