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- EMDB-30854: Human Calcium-Sensing Receptor bound with L-Trp -

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Basic information

Entry
Database: EMDB / ID: EMD-30854
TitleHuman Calcium-Sensing Receptor bound with L-Trp
Map data
Sample
  • Complex: Human Calcium-Sensing Receptor bound with L-Trp
    • Protein or peptide: Extracellular calcium-sensing receptor
  • Ligand: TRYPTOPHAN
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsGPCR / class C / calcium sensing receptor / MEMBRANE 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: 4.4 Å
AuthorsLing SL / Tian CL
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Cell Res / Year: 2021
Title: Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca ions and L-tryptophan.
Authors: Shenglong Ling / Pan Shi / Sanling Liu / Xianyu Meng / Yingxin Zhou / Wenjing Sun / Shenghai Chang / Xing Zhang / Longhua Zhang / Chaowei Shi / Demeng Sun / Lei Liu / Changlin Tian /
Abstract: The human calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) responsible for maintaining Ca homeostasis in the blood. The general consensus is that extracellular Ca is ...The human calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) responsible for maintaining Ca homeostasis in the blood. The general consensus is that extracellular Ca is the principal agonist of CaSR. Aliphatic and aromatic L-amino acids, such as L-Phe and L-Trp, increase the sensitivity of CaSR towards Ca and are considered allosteric activators. Crystal structures of the extracellular domain (ECD) of CaSR dimer have demonstrated Ca and L-Trp binding sites and conformational changes of the ECD upon Ca/L-Trp binding. However, it remains to be understood at the structural level how Ca/L-Trp binding to the ECD leads to conformational changes in transmembrane domains (TMDs) and consequent CaSR activation. Here, we determined the structures of full-length human CaSR in the inactive state, Ca- or L-Trp-bound states, and Ca/L-Trp-bound active state using single-particle cryo-electron microscopy. Structural studies demonstrate that L-Trp binding induces the closure of the Venus flytrap (VFT) domain of CaSR, bringing the receptor into an intermediate active state. Ca binding relays the conformational changes from the VFT domains to the TMDs, consequently inducing close contact between the two TMDs of dimeric CaSR, activating the receptor. Importantly, our structural and functional studies reveal that Ca ions and L-Trp activate CaSR cooperatively. Amino acids are not able to activate CaSR alone, but can promote the receptor activation in the presence of Ca. Our data provide complementary insights into the activation of class C GPCRs and may aid in the development of novel drugs targeting CaSR.
History
DepositionJan 6, 2021-
Header (metadata) releaseMar 10, 2021-
Map releaseMar 10, 2021-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.013
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  • Surface view with fitted model
  • Atomic models: PDB-7dtu
  • Surface level: 0.013
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7dtu
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30854.png

Downloads & links

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Map

FileDownload / File: emd_30854.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.01 Å/pix.
x 320 pix.
= 323.2 Å		1.01 Å/pix.
x 320 pix.
= 323.2 Å		1.01 Å/pix.
x 320 pix.
= 323.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.01 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.012 / Movie #1: 0.013
Minimum - Maximum-0.00865396 - 0.036331512
Average (Standard dev.)0.00027207413 (±0.001663221)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 323.2 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.011.011.01
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z323.200323.200323.200
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ300300300
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.0090.0360.000

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Supplemental data

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Sample components

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Entire : Human Calcium-Sensing Receptor bound with L-Trp

EntireName: Human Calcium-Sensing Receptor bound with L-Trp
Components
  • Complex: Human Calcium-Sensing Receptor bound with L-Trp
    • Protein or peptide: Extracellular calcium-sensing receptor
  • Ligand: TRYPTOPHAN
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Human Calcium-Sensing Receptor bound with L-Trp

SupramoleculeName: Human Calcium-Sensing Receptor bound with L-Trp / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Extracellular calcium-sensing receptor

MacromoleculeName: Extracellular calcium-sensing receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 123.520828 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDENLYFQG YGPDQRAQKK GDIILGGLFP IHFGVAAKDQ DLKSRPESVE CIRYNFRGFR WLQAMIFAI EEINSSPALL PNLTLGYRIF DTCNTVSKAL EATLSFVAQN KIDSLNLDEF CNCSEHIPST IAVVGATGSG V STAVANLL ...String:
MKTIIALSYI FCLVFADYKD DDDENLYFQG YGPDQRAQKK GDIILGGLFP IHFGVAAKDQ DLKSRPESVE CIRYNFRGFR WLQAMIFAI EEINSSPALL PNLTLGYRIF DTCNTVSKAL EATLSFVAQN KIDSLNLDEF CNCSEHIPST IAVVGATGSG V STAVANLL GLFYIPQVSY ASSSRLLSNK NQFKSFLRTI PNDEHQATAM ADIIEYFRWN WVGTIAADDD YGRPGIEKFR EE AEERDIC IDFSELISQY SDEEEIQHVV EVIQNSTAKV IVVFSSGPDL EPLIKEIVRR NITGKIWLAS EAWASSSLIA MPQ YFHVVG GTIGFALKAG QIPGFREFLK KVHPRKSVHN GFAKEFWEET FNCHLQEGAK GPLPVDTFLR GHEESGDRFS NSST AFRPL CTGDENISSV ETPYIDYTHL RISYNVYLAV YSIAHALQDI YTCLPGRGLF TNGSCADIKK VEAWQVLKHL RHLNF TNNM GEQVTFDECG DLVGNYSIIN WHLSPEDGSI VFKEVGYYNV YAKKGERLFI NEEKILWSGF SREVPFSNCS RDCLAG TRK GIIEGEPTCC FECVECPDGE YSDETDASAC NKCPDDFWSN ENHTSCIAKE IEFLSWTEPF GIALTLFAVL GIFLTAF VL GVFIKFRNTP IVKATNRELS YLLLFSLLCC FSSSLFFIGE PQDWTCRLRQ PAFGISFVLC ISCILVKTNR VLLVFEAK I PTSFHRKWWG LNLQFLLVFL CTFMQIVICV IWLYTAPPSS YRNQELEDEI IFITCHEGSL MALGFLIGYT CLLAAICFF FAFKSRKLPE NFNEAKFITF SMLIFFIVWI SFIPAYASTY GKFVSAVEVI AILAASFGLL ACIFFNKIYI ILFKPSRNTI EEVRCSTAA HAFKVAARAT LRRSNVSRKR SSSLGGSTGS TPSSSISSKS NSEDPFPQPE RQKQQQPLAL TQQEQQQQPL T LPQQQRSQ QQPRCKQKVI FGSGTVTFSL SFDEPQKNAM AHRNSTHQNS LEAQKSSDTL TRHEPLLPLQ CGETDLDLTV QE TGLQGPV GGDQRPEVED PEELSPALVV SSSQSFVISG GGSTVTENVV NSHHHHHHHH HH

UniProtKB: Extracellular calcium-sensing receptor

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Macromolecule #3: TRYPTOPHAN

MacromoleculeName: TRYPTOPHAN / type: ligand / ID: 3 / Number of copies: 2 / Formula: TRP
Molecular weightTheoretical: 204.225 Da
Chemical component information

ChemComp-TRP:
TRYPTOPHAN

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

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / 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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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

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 56.5 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: DIFFRACTION
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 240292
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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