+
Open data
-
Basic information
Entry | Database: EMDB / ID: EMD-30854 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | Human Calcium-Sensing Receptor bound with L-Trp | |||||||||
![]() | ||||||||||
![]() |
| |||||||||
Function / homology | ![]() bile acid secretion / chemosensory behavior / cellular response to peptide / response to fibroblast growth factor / 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 / cellular response to peptide / response to fibroblast growth factor / 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 / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | ![]() ![]() | |||||||||
![]() | Ling SL / Tian CL / Shi P / Liu SL / Meng XY / Liu L / Sun DM / Shi CW | |||||||||
Funding support | ![]()
| |||||||||
![]() | ![]() 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 |
|
-
Structure visualization
Movie |
![]() |
---|---|
Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
-
Downloads & links
-EMDB archive
Map data | ![]() | 8.9 MB | ![]() | |
---|---|---|---|---|
Header (meta data) | ![]() ![]() | 11.1 KB 11.1 KB | Display Display | ![]() |
Images | ![]() | 66.5 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7dtuMC ![]() 7dttC ![]() 7dtvC ![]() 7dtwC M: atomic model generated by this map C: citing same article ( |
---|---|
Similar structure data |
-
Links
EMDB pages | ![]() ![]() |
---|---|
Related items in Molecule of the Month |
-
Map
File | ![]() | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Voxel size | X=Y=Z: 1.01 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
|
-Supplemental data
-
Sample components
-Entire : Human Calcium-Sensing Receptor bound with L-Trp
Entire | Name: Human Calcium-Sensing Receptor bound with L-Trp |
---|---|
Components |
|
-Supramolecule #1: Human Calcium-Sensing Receptor bound with L-Trp
Supramolecule | Name: Human Calcium-Sensing Receptor bound with L-Trp / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
---|---|
Source (natural) | Organism: ![]() ![]() |
Recombinant expression | Organism: ![]() ![]() ![]() |
-Macromolecule #1: Extracellular calcium-sensing receptor
Macromolecule | Name: Extracellular calcium-sensing receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
---|---|
Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 123.520828 KDa |
Recombinant expression | Organism: ![]() ![]() ![]() |
Sequence | String: 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 |
-Macromolecule #3: TRYPTOPHAN
Macromolecule | Name: TRYPTOPHAN / type: ligand / ID: 3 / Number of copies: 2 / Formula: TRP |
---|---|
Molecular weight | Theoretical: 204.225 Da |
Chemical component information | ![]() ChemComp-TRP: |
-Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 6 / Formula: NAG |
---|---|
Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Experimental details
-Structure determination
Method | ![]() |
---|---|
![]() | ![]() |
Aggregation state | particle |
-
Sample preparation
Buffer | pH: 7.5 |
---|---|
Vitrification | Cryogen name: ETHANE |
-
Electron microscopy
Microscope | FEI TITAN KRIOS |
---|---|
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: SPOT SCAN / Imaging mode: DIFFRACTION![]() |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 56.5 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
-
Image processing
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
---|---|
Final angle assignment | Type: MAXIMUM LIKELIHOOD |
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 240292 |