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- EMDB-30857: Human calcium sensing receptor adopts an inactive open-open confo... -

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Basic information

Entry
Database: EMDB / ID: EMD-30857
TitleHuman calcium sensing receptor adopts an inactive open-open conformation
Map data
Sample
  • Complex: Human Calcium-Sensing Receptor in an inactive state
    • Protein or peptide: human calcium sensing receptorCalcium-sensing receptor
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.8 Å
AuthorsLing SL / Tian CL / Shi P / Liu SL / Meng XY / Liu L / Sun DM / Shi CW
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) releaseJan 12, 2022-
Map releaseJan 12, 2022-
UpdateJan 12, 2022-
Current statusJan 12, 2022Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.009
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.009
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30857.png

Downloads & links

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Map

FileDownload / File: emd_30857.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.06 Å
Density
Contour LevelBy AUTHOR: 0.009 / Movie #1: 0.009
Minimum - Maximum-0.005414542 - 0.020654993
Average (Standard dev.)0.00015711944 (±0.001128888)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 339.19998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.061.061.06
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z339.200339.200339.200
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.0050.0210.000

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Supplemental data

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Sample components

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Entire : Human Calcium-Sensing Receptor in an inactive state

EntireName: Human Calcium-Sensing Receptor in an inactive state
Components
  • Complex: Human Calcium-Sensing Receptor in an inactive state
    • Protein or peptide: human calcium sensing receptorCalcium-sensing receptor

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

SupramoleculeName: Human Calcium-Sensing Receptor in an inactive state / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)

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Macromolecule #1: human calcium sensing receptor

MacromoleculeName: human calcium sensing receptor / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
SequenceString: MKTIIALSYI FCLVFADYKD DDDENLYFQG YGPDQRAQKK GDIILGGLFP IHFGVAAKDQ DLKSRPESVE CIRYNFRGFR WLQAMIFAIE EINSSPALLP NLTLGYRIFD TCNTVSKALE ATLSFVAQNK IDSLNLDEFC NCSEHIPSTI AVVGATGSGV STAVANLLGL ...String:
MKTIIALSYI FCLVFADYKD DDDENLYFQG YGPDQRAQKK GDIILGGLFP IHFGVAAKDQ DLKSRPESVE CIRYNFRGFR WLQAMIFAIE EINSSPALLP NLTLGYRIFD TCNTVSKALE ATLSFVAQNK IDSLNLDEFC NCSEHIPSTI AVVGATGSGV STAVANLLGL FYIPQVSYAS SSRLLSNKNQ FKSFLRTIPN DEHQATAMAD IIEYFRWNWV GTIAADDDYG RPGIEKFREE AEERDICIDF SELISQYSDE EEIQHVVEVI QNSTAKVIVV FSSGPDLEPL IKEIVRRNIT GKIWLASEAW ASSSLIAMPQ YFHVVGGTIG FALKAGQIPG FREFLKKVHP RKSVHNGFAK EFWEETFNCH LQEGAKGPLP VDTFLRGHEE SGDRFSNSST AFRPLCTGDE NISSVETPYI DYTHLRISYN VYLAVYSIAH ALQDIYTCLP GRGLFTNGSC ADIKKVEAWQ VLKHLRHLNF TNNMGEQVTF DECGDLVGNY SIINWHLSPE DGSIVFKEVG YYNVYAKKGE RLFINEEKIL WSGFSREVPF SNCSRDCLAG TRKGIIEGEP TCCFECVECP DGEYSDETDA SACNKCPDDF WSNENHTSCI AKEIEFLSWT EPFGIALTLF AVLGIFLTAF VLGVFIKFRN TPIVKATNRE LSYLLLFSLL CCFSSSLFFI GEPQDWTCRL RQPAFGISFV LCISCILVKT NRVLLVFEAK IPTSFHRKWW GLNLQFLLVF LCTFMQIVIC VIWLYTAPPS SYRNQELEDE IIFITCHEGS LMALGFLIGY TCLLAAICFF FAFKSRKLPE NFNEAKFITF SMLIFFIVWI SFIPAYASTY GKFVSAVEVI AILAASFGLL ACIFFNKIYI ILFKPSRNTI EEVRCSTAAH AFKVAARATL RRSNVSRKRS SSLGGSTGST PSSSISSKSN SEDPFPQPER QKQQQPLALT QQEQQQQPLT LPQQQRSQQQ PRCKQKVIFG SGTVTFSLSF DEPQKNAMAH RNSTHQNSLE AQKSSDTLTR HEPLLPLQCG ETDLDLTVQE TGLQGPVGGD QRPEVEDPEE LSPALVVSSS QSFVISGGGS TVTENVVNSH HHHHHHHHH

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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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: DIFFRACTION
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 62.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 6.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 210908

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