View source for 9axf


==Structure of human calcium-sensing receptor in complex with chimeric Gq (miniGisq) protein in detergent==
<StructureSection load='9axf' size='340' side='right'caption='[[9axf]], [[Resolution|resolution]] 3.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9axf]] is a 7 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Lama_glama Lama glama] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9AXF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9AXF FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9IG:3-(2-chlorophenyl)-~{N}-[(1~{R})-1-(3-methoxyphenyl)ethyl]propan-1-amine'>9IG</scene>, <scene name='pdbligand=AV0:(2~{R},3~{R},4~{S},5~{S},6~{R})-2-[(2~{R},3~{S},4~{R},5~{R},6~{R})-6-[2-decyl-2-[[(2~{R},3~{R},4~{R},5~{S},6~{R})-6-(hydroxymethyl)-5-[(2~{R},3~{R},4~{S},5~{S},6~{R})-6-(hydroxymethyl)-3,4,5-tris(oxidanyl)oxan-2-yl]oxy-3,4-bis(oxidanyl)oxan-2-yl]oxymethyl]dodecoxy]-2-(hydroxymethyl)-4,5-bis(oxidanyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol'>AV0</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=TCR:CYCLOMETHYLTRYPTOPHAN'>TCR</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</scene></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=9axf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9axf OCA], [https://pdbe.org/9axf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9axf RCSB], [https://www.ebi.ac.uk/pdbsum/9axf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9axf 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) detects fluctuations in the extracellular Ca(2+) concentration and maintains Ca(2+) homeostasis(1,2). It also mediates diverse cellular processes not associated with Ca(2+) balance(3-5). The functional pleiotropy of CaSR arises in part from its ability to signal through several G-protein subtypes(6). We determined structures of CaSR in complex with G proteins from three different subfamilies: G(q), G(i) and G(s). We found that the homodimeric CaSR of each complex couples to a single G protein through a common mode. This involves the C-terminal helix of each Galpha subunit binding to a shallow pocket that is formed in one CaSR subunit by all three intracellular loops (ICL1-ICL3), an extended transmembrane helix 3 and an ordered C-terminal region. G-protein binding expands the transmembrane dimer interface, which is further stabilized by phospholipid. The restraint imposed by the receptor dimer, in combination with ICL2, enables G-protein activation by facilitating conformational transition of Galpha. We identified a single Galpha residue that determines G(q) and G(s) versus G(i) selectivity. The length and flexibility of ICL2 allows CaSR to bind all three Galpha subtypes, thereby conferring capacity for promiscuous G-protein coupling.

Promiscuous G-protein activation by the calcium-sensing receptor.,Zuo H, Park J, Frangaj A, Ye J, Lu G, Manning JJ, Asher WB, Lu Z, Hu GB, Wang L, Mendez J, Eng E, Zhang Z, Lin X, Grassucci R, Hendrickson WA, Clarke OB, Javitch JA, Conigrave AD, Fan QR Nature. 2024 May;629(8011):481-488. doi: 10.1038/s41586-024-07331-1. Epub 2024 , Apr 17. PMID:38632411<ref>PMID:38632411</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9axf" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Lama glama]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Asher WB]]
[[Category: Clarke OB]]
[[Category: Conigrave AD]]
[[Category: Eng E]]
[[Category: Fan QR]]
[[Category: Frangaj A]]
[[Category: Grasucci R]]
[[Category: Hendrickson WA]]
[[Category: Hu G]]
[[Category: Javitch JA]]
[[Category: Lin X]]
[[Category: Lu G]]
[[Category: Lu Z]]
[[Category: Manning JJ]]
[[Category: Mendez J]]
[[Category: Park J]]
[[Category: Wang L]]
[[Category: Ye J]]
[[Category: Zhang Z]]
[[Category: Zuo H]]