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- EMDB-30644: Structure of Calcium-Sensing Receptor in complex with NPS-2143 -

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Basic information

Entry
Database: EMDB / ID: EMD-30644
TitleStructure of Calcium-Sensing Receptor in complex with NPS-2143
Map datamap
Sample
  • Cell: Calcium-Sensing Receptor from Gallus gallus with Ca2+/L-Trp/NPS-2143
    • Protein or peptide: Calcium-Sensing Receptor
  • Ligand: CHLORIDE ION
  • Ligand: CALCIUM ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: TRYPTOPHAN
  • Ligand: 2-chloro-6-[(2R)-2-hydroxy-3-{[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino}propoxy]benzonitrile
  • Ligand: water
KeywordsCalcium-Sensing Receptor / CaSR / NPS-2143 / MEMBRANE PROTEIN
Biological speciesGallus gallus (chicken)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsWen TL / Yang X
CitationJournal: Sci Adv / Year: 2021
Title: Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor.
Authors: Tianlei Wen / Ziyu Wang / Xiaozhe Chen / Yue Ren / Xuhang Lu / Yangfei Xing / Jing Lu / Shenghai Chang / Xing Zhang / Yuequan Shen / Xue Yang /
Abstract: Calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) that plays an important role in calcium homeostasis and parathyroid hormone secretion. Here, we present multiple cryo- ...Calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) that plays an important role in calcium homeostasis and parathyroid hormone secretion. Here, we present multiple cryo-electron microscopy structures of full-length CaSR in distinct ligand-bound states. Ligands (Ca and l-tryptophan) bind to the extracellular domain of CaSR and induce large-scale conformational changes, leading to the closure of two heptahelical transmembrane domains (7TMDs) for activation. The positive modulator (evocalcet) and the negative allosteric modulator (NPS-2143) occupy the similar binding pocket in 7TMD. The binding of NPS-2143 causes a considerable rearrangement of two 7TMDs, forming an inactivated TM6/TM6 interface. Moreover, a total of 305 disease-causing missense mutations of CaSR have been mapped to the structure in the active state, creating hotspot maps of five clinical endocrine disorders. Our results provide a structural framework for understanding the activation, allosteric modulation mechanism, and disease therapy for class C GPCRs.
History
DepositionOct 27, 2020-
Header (metadata) releaseJun 16, 2021-
Map releaseJun 16, 2021-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.4
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.4
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7dd5
  • Surface level: 0.4
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30644.png

Downloads & links

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Map

FileDownload / File: emd_30644.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmap
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.01 Å/pix.
x 280 pix.
= 283.92 Å		1.01 Å/pix.
x 280 pix.
= 283.92 Å		1.01 Å/pix.
x 280 pix.
= 283.92 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.014 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3 / Movie #1: 0.4
Minimum - Maximum-1.6494915 - 2.8885117
Average (Standard dev.)-0.0023474495 (±0.08150416)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 283.92 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0141.0141.014
M x/y/z280280280
origin x/y/z0.0000.0000.000
length x/y/z283.920283.920283.920
α/β/γ90.00090.00090.000
start NX/NY/NZ1229869
NX/NY/NZ377377377
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS280280280
D min/max/mean-1.6492.889-0.002

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Supplemental data

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Additional map: TM

Fileemd_30644_additional_1.map
AnnotationTM
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: ECD

Fileemd_30644_additional_2.map
AnnotationECD
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Calcium-Sensing Receptor from Gallus gallus with Ca2+/L-Trp/NPS-2143

EntireName: Calcium-Sensing Receptor from Gallus gallus with Ca2+/L-Trp/NPS-2143
Components
  • Cell: Calcium-Sensing Receptor from Gallus gallus with Ca2+/L-Trp/NPS-2143
    • Protein or peptide: Calcium-Sensing Receptor
  • Ligand: CHLORIDE ION
  • Ligand: CALCIUM ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: TRYPTOPHAN
  • Ligand: 2-chloro-6-[(2R)-2-hydroxy-3-{[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino}propoxy]benzonitrile
  • Ligand: water

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Supramolecule #1: Calcium-Sensing Receptor from Gallus gallus with Ca2+/L-Trp/NPS-2143

SupramoleculeName: Calcium-Sensing Receptor from Gallus gallus with Ca2+/L-Trp/NPS-2143
type: cell / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Gallus gallus (chicken)

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Macromolecule #1: Calcium-Sensing Receptor

MacromoleculeName: Calcium-Sensing Receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Gallus gallus (chicken)
Molecular weightTheoretical: 119.314234 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MTLYSCCLIL LLFTWNTAAY GPNQRAQKKG DIILGGLFPI HFGVAAKDQD LKSRPESVEC IRYNFRGFRW LQAMIFAIEE INNSPNLLP NMTLGYRIFD TCNTVSKALE ATLSFVAQNK IDSLNLDEFC NCSEHIPSTI AVVGATGSGV STAVANLLGL F YIPQVSYA ...String:
MTLYSCCLIL LLFTWNTAAY GPNQRAQKKG DIILGGLFPI HFGVAAKDQD LKSRPESVEC IRYNFRGFRW LQAMIFAIEE INNSPNLLP NMTLGYRIFD TCNTVSKALE ATLSFVAQNK IDSLNLDEFC NCSEHIPSTI AVVGATGSGV STAVANLLGL F YIPQVSYA SSSRLLSNKN QFKSFLRTIP NDEHQATAMA DIIEYFRWNW VGTIAADDDY GRPGIEKFRE EAEERDICID FS ELISQYS DEEEIQQVVE VIQNSTARVI VVFSSGPDLE PLIKEIVRRN ITGKIWLASE AWASSSLIAM PEFFRVIGST IGF ALKAGQ IPGFREFLQK VHPKKSANNG FAKEFWEETF NCYLPSESKN SPASASFHKA HEEGLGAGNG TAAFRPPCTG DENI TSVET PYMDFTHLRI SYNVYLAVYS IAHALQDIYT CTPGKGLFTN GSCADIKKVE AWQVLKHLRH LNFTSNMGEQ VDFDE FGDL VGNYSIINWH LSPEDGSVVF EEVGHYNVYA KKGERLFINE NKILWSGFSK EVPFSNCSRD CLPGTRKGII EGEPTC CFE CVDCPDGEYS DETDASACDK CPEDYWSNEN HTSCIPKQIE FLSWTEPFGI ALTLFAVLGI FLTSFVLGVF TKFRNTP IV KATNRELSYL LLFSLLCCFS SSLFFIGEPQ NWTCRLRQPA FGISFVLCIS CILVKTNRVL LVFEAKIPTS LHRKWWGL N LQFLLVFLCT FVQIVICVIW LYTAPPSSYR NHELEDEIIF ITCHEGSLMA LGFLIGYTCL LAAICFFFAF KSRKLPENF NEAKFITFSM LIFFIVWISF IPAYASTYGK FVSAVEVIAI LAASFGLLAC IFFNKVYIIL FKPSRNTIEE VRCSTAAHAF KVAARATLR RSNVSRKRSN SLGGSTGSTP SSSISSKSNH EDPFPLPASA ERQRQQQRGC KQKVSFGSGT VTLSLSFEEP Q KNAMANRN AKRRNSLEAQ NSDDSLMRHR ALLALQNSES LSAEPGFQTA SSPETSSQES VVGDNKEEVP NPEAEPSLPS AN SRNFIGT GGSSVTENTV HSLESALEVL FQ

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Macromolecule #3: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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Macromolecule #4: CALCIUM ION

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

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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Macromolecule #6: TRYPTOPHAN

MacromoleculeName: TRYPTOPHAN / type: ligand / ID: 6 / Number of copies: 2 / Formula: TRP
Molecular weightTheoretical: 204.225 Da
Chemical component information

ChemComp-TRP:
TRYPTOPHAN

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Macromolecule #7: 2-chloro-6-[(2R)-2-hydroxy-3-{[2-methyl-1-(naphthalen-2-yl)propan...

MacromoleculeName: 2-chloro-6-[(2R)-2-hydroxy-3-{[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino}propoxy]benzonitrile
type: ligand / ID: 7 / Number of copies: 2 / Formula: YP1
Molecular weightTheoretical: 408.921 Da
Chemical component information

ChemComp-YP1:
2-chloro-6-[(2R)-2-hydroxy-3-{[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino}propoxy]benzonitrile

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Macromolecule #8: water

MacromoleculeName: water / type: ligand / ID: 8 / Number of copies: 2 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI TITAN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / 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

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 86921
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-7dd5:
Structure of Calcium-Sensing Receptor in complex with NPS-2143

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