View source for 7dtt


==Human Calcium-Sensing Receptor bound with calcium ions==
<StructureSection load='7dtt' size='340' side='right'caption='[[7dtt]], [[Resolution|resolution]] 3.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7dtt]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7DTT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7DTT FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CASR, GPRC2A, PCAR1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7dtt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7dtt OCA], [https://pdbe.org/7dtt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7dtt RCSB], [https://www.ebi.ac.uk/pdbsum/7dtt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7dtt ProSAT]</span></td></tr>
</table>
== Disease ==
[[https://www.uniprot.org/uniprot/CASR_HUMAN CASR_HUMAN]] Autosomal dominant hypocalcemia;Familial isolated hypoparathyroidism due to impaired PTH secretion;Neonatal severe primary hyperparathyroidism;Familial hypocalciuric hypercalcemia type 1;Bartter syndrome with hypocalcemia. The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  Disease susceptibility is associated with variations affecting the gene represented in this entry.  Homozygous defects in CASR can be a cause of primary hyperparathyroidism in adulthood. Patients suffer from osteoporosis and renal calculi, have marked hypercalcemia and increased serum PTH concentrations. 
== Function ==
[[https://www.uniprot.org/uniprot/CASR_HUMAN CASR_HUMAN]] Senses changes in the extracellular concentration of calcium ions. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The human calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) responsible for maintaining Ca(2+) homeostasis in the blood. The general consensus is that extracellular Ca(2+) 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(2+) and are considered allosteric activators. Crystal structures of the extracellular domain (ECD) of CaSR dimer have demonstrated Ca(2+) and L-Trp binding sites and conformational changes of the ECD upon Ca(2+)/L-Trp binding. However, it remains to be understood at the structural level how Ca(2+)/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(2+)- or L-Trp-bound states, and Ca(2+)/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(2+) 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(2+) 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(2+). Our data provide complementary insights into the activation of class C GPCRs and may aid in the development of novel drugs targeting CaSR.

Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca(2+) ions and L-tryptophan.,Ling S, Shi P, Liu S, Meng X, Zhou Y, Sun W, Chang S, Zhang X, Zhang L, Shi C, Sun D, Liu L, Tian C Cell Res. 2021 Feb 18. pii: 10.1038/s41422-021-00474-0. doi:, 10.1038/s41422-021-00474-0. PMID:33603117<ref>PMID:33603117</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7dtt" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Ling, S L]]
[[Category: Liu, L]]
[[Category: Liu, S L]]
[[Category: Meng, X Y]]
[[Category: Shi, C W]]
[[Category: Shi, P]]
[[Category: Sun, D M]]
[[Category: Tian, C L]]
[[Category: Calcium sensing receptor]]
[[Category: Class c]]
[[Category: Gpcr]]
[[Category: Membrane protein]]