View source for 8szg


==Cryo-EM structure of cinacalcet-bound human calcium-sensing receptor CaSR-Gq complex in lipid nanodiscs==
<StructureSection load='8szg' size='340' side='right'caption='[[8szg]], [[Resolution|resolution]] 3.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8szg]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8SZG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8SZG 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]] 3.6&#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=PCW:1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>PCW</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SPM:SPERMINE'>SPM</scene>, <scene name='pdbligand=TRP:TRYPTOPHAN'>TRP</scene>, <scene name='pdbligand=YP4:N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine'>YP4</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=8szg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8szg OCA], [https://pdbe.org/8szg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8szg RCSB], [https://www.ebi.ac.uk/pdbsum/8szg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8szg ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor(1) (GPCR) that has a central role in regulating systemic calcium homeostasis(2,3). Here we use cryo-electron microscopy and functional assays to investigate the activation of human CaSR embedded in lipid nanodiscs and its coupling to functional G(i) versus G(q) proteins in the presence and absence of the calcimimetic drug cinacalcet. High-resolution structures show that both G(i) and G(q) drive additional conformational changes in the activated CaSR dimer to stabilize a more extensive asymmetric interface of the seven-transmembrane domain (7TM) that involves key protein-lipid interactions. Selective G(i) and G(q) coupling by the receptor is achieved through substantial rearrangements of intracellular loop 2 and the C terminus, which contribute differentially towards the binding of the two G-protein subtypes, resulting in distinct CaSR-G-protein interfaces. The structures also reveal that natural polyamines target multiple sites on CaSR to enhance receptor activation by zipping negatively charged regions between two protomers. Furthermore, we find that the amino acid L-tryptophan, a well-known ligand of CaSR extracellular domains, occupies the 7TM bundle of the G-protein-coupled protomer at the same location as cinacalcet and other allosteric modulators. Together, these results provide a framework for G-protein activation and selectivity by CaSR, as well as its allosteric modulation by endogenous and exogenous ligands.

Allosteric modulation and G-protein selectivity of the Ca(2+)-sensing receptor.,He F, Wu CG, Gao Y, Rahman SN, Zaoralova M, Papasergi-Scott MM, Gu TJ, Robertson MJ, Seven AB, Li L, Mathiesen JM, Skiniotis G Nature. 2024 Feb;626(8001):1141-1148. doi: 10.1038/s41586-024-07055-2. Epub 2024 , Feb 7. PMID:38326620<ref>PMID:38326620</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 8szg" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Gao Y]]
[[Category: He F]]
[[Category: Skiniotis G]]
[[Category: Wu C]]