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- EMDB-30646: Structure of Calcium-Sensing Receptor in an inactive state -

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Basic information

Entry
Database: EMDB / ID: EMD-30646
TitleStructure of Calcium-Sensing Receptor in an inactive state
Map data
Sample
  • Cell: Calcium-Sensing Receptor in an inactive state
    • Protein or peptide: Calcium-Sensing Receptor, CaSR
Biological speciesGallus gallus (chicken)
Methodsingle particle reconstruction / cryo EM / Resolution: 7.2 Å
AuthorsWen TL / Yang X / Shen YQ
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-
UpdateJun 16, 2021-
Current statusJun 16, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.297
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.297
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30646.png

Downloads & links

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Map

FileDownload / File: emd_30646.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.014 Å
Density
Contour LevelBy AUTHOR: 0.297 / Movie #1: 0.297
Minimum - Maximum-0.23453961 - 0.7799185
Average (Standard dev.)-0.003883357 (±0.054298546)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 324.48 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0141.0141.014
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z324.480324.480324.480
α/β/γ90.00090.00090.000
start NX/NY/NZ1229869
NX/NY/NZ377377377
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.2350.780-0.004

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Supplemental data

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Sample components

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Entire : Calcium-Sensing Receptor in an inactive state

EntireName: Calcium-Sensing Receptor in an inactive state
Components
  • Cell: Calcium-Sensing Receptor in an inactive state
    • Protein or peptide: Calcium-Sensing Receptor, CaSR

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Supramolecule #1: Calcium-Sensing Receptor in an inactive state

SupramoleculeName: Calcium-Sensing Receptor in an inactive state / type: cell / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Gallus gallus (chicken)

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Macromolecule #1: Calcium-Sensing Receptor, CaSR

MacromoleculeName: Calcium-Sensing Receptor, CaSR / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Gallus gallus (chicken)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MTLYSCCLIL LLFTWNTAAY GPNQRAQKKG DIILGGLFPI HFGVAAKDQD LKSRPESVEC IRYNFRGFRW LQAMIFAIEE INNSPNLLPN MTLGYRIFDT CNTVSKALEA TLSFVAQNKI DSLNLDEFCN CSEHIPSTIA VVGATGSGVS TAVANLLGLF YIPQVSYASS ...String:
MTLYSCCLIL LLFTWNTAAY GPNQRAQKKG DIILGGLFPI HFGVAAKDQD LKSRPESVEC IRYNFRGFRW LQAMIFAIEE INNSPNLLPN MTLGYRIFDT CNTVSKALEA TLSFVAQNKI DSLNLDEFCN CSEHIPSTIA VVGATGSGVS TAVANLLGLF YIPQVSYASS SRLLSNKNQF KSFLRTIPND EHQATAMADI IEYFRWNWVG TIAADDDYGR PGIEKFREEA EERDICIDFS ELISQYSDEE EIQQVVEVIQ NSTARVIVVF SSGPDLEPLI KEIVRRNITG KIWLASEAWA SSSLIAMPEF FRVIGSTIGF ALKAGQIPGF REFLQKVHPK KSANNGFAKE FWEETFNCYL PSESKNSPAS ASFHKAHEEG LGAGNGTAAF RPPCTGDENI TSVETPYMDF THLRISYNVY LAVYSIAHAL QDIYTCTPGK GLFTNGSCAD IKKVEAWQVL KHLRHLNFTS NMGEQVDFDE FGDLVGNYSI INWHLSPEDG SVVFEEVGHY NVYAKKGERL FINENKILWS GFSKEVPFSN CSRDCLPGTR KGIIEGEPTC CFECVDCPDG EYSDETDASA CDKCPEDYWS NENHTSCIPK QIEFLSWTEP FGIALTLFAV LGIFLTSFVL GVFTKFRNTP IVKATNRELS YLLLFSLLCC FSSSLFFIGE PQNWTCRLRQ PAFGISFVLC ISCILVKTNR VLLVFEAKIP TSLHRKWWGL NLQFLLVFLC TFVQIVICVI WLYTAPPSSY RNHELEDEII FITCHEGSLM ALGFLIGYTC LLAAICFFFA FKSRKLPENF NEAKFITFSM LIFFIVWISF IPAYASTYGK FVSAVEVIAI LAASFGLLAC IFFNKVYIIL FKPSRNTIEE VRCSTAAHAF KVAARATLRR SNVSRKRSNS LGGSTGSTPS SSISSKSNHE DPFPLPASAE RQRQQQRGCK QKVSFGSGTV TLSLSFEEPQ KNAMANRNAK RRNSLEAQNS DDSLMRHRAL LALQNSESLS AEPGFQTASS PETSSQESVV GDNKEEVPNP EAEPSLPSAN SRNFIGTGGS SVTENTVHSL ESALEVLFQ

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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
GridModel: Quantifoil R2/1 / Material: COPPER / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE
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: COUNTING / 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: 25.0 µm / Nominal defocus min: 5.0 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 7.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 80104
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL

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