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==Structure of positive allosteric modulator-free active human calcium-sensing receptor==
<StructureSection load='7sim' size='340' side='right'caption='[[7sim]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7SIM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SIM 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]] 2.7&#8491;</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=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></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=7sim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7sim OCA], [https://pdbe.org/7sim PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7sim RCSB], [https://www.ebi.ac.uk/pdbsum/7sim PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7sim ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The human extracellular calcium-sensing (CaS) receptor controls plasma Ca(2+) levels and contributes to nutrient-dependent maintenance and metabolism of diverse organs. Allosteric modulation of the CaS receptor corrects disorders of calcium homeostasis. Here, we report the cryogenic-electron microscopy reconstructions of a near-full-length CaS receptor in the absence and presence of allosteric modulators. Activation of the homodimeric CaS receptor requires a break in the transmembrane 6 (TM6) helix of each subunit, which facilitates the formation of a TM6-mediated homodimer interface and expansion of homodimer interactions. This transformation in TM6 occurs without a positive allosteric modulator. Two modulators with opposite functional roles bind to overlapping sites within the transmembrane domain through common interactions, acting to stabilize distinct rotamer conformations of key residues on the TM6 helix. The positive modulator reinforces TM6 distortion and maximizes subunit contact to enhance receptor activity, while the negative modulator strengthens an intact TM6 to dampen receptor function. In both active and inactive states, the receptor displays symmetrical transmembrane conformations that are consistent with its homodimeric assembly.

Symmetric activation and modulation of the human calcium-sensing receptor.,Park J, Zuo H, Frangaj A, Fu Z, Yen LY, Zhang Z, Mosyak L, Slavkovich VN, Liu J, Ray KM, Cao B, Vallese F, Geng Y, Chen S, Grassucci R, Dandey VP, Tan YZ, Eng E, Lee Y, Kloss B, Liu Z, Hendrickson WA, Potter CS, Carragher B, Graziano J, Conigrave AD, Frank J, Clarke OB, Fan QR Proc Natl Acad Sci U S A. 2021 Dec 21;118(51). pii: 2115849118. doi:, 10.1073/pnas.2115849118. PMID:34916296<ref>PMID:34916296</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7sim" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Cao B]]
[[Category: Carragher B]]
[[Category: Chen S]]
[[Category: Clarke OB]]
[[Category: Conigrave AD]]
[[Category: Dandey VP]]
[[Category: Eng E]]
[[Category: Fan QR]]
[[Category: Frangaj A]]
[[Category: Frank J]]
[[Category: Fu Z]]
[[Category: Geng Y]]
[[Category: Grassucci R]]
[[Category: Graziano J]]
[[Category: Hendrickson WA]]
[[Category: Kloss B]]
[[Category: Lee Y]]
[[Category: Liu J]]
[[Category: Liu Z]]
[[Category: Mosyak L]]
[[Category: Park J]]
[[Category: Potter CS]]
[[Category: Ray KM]]
[[Category: Slavkovich VN]]
[[Category: Tan YZ]]
[[Category: Vallese F]]
[[Category: Yen LY]]
[[Category: Zhang Z]]
[[Category: Zuo H]]