9c1p
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | The entry | + | ==Structure of Calcium-Sensing Receptor in complex with positive allosteric modulator '6218== |
| + | <StructureSection load='9c1p' size='340' side='right'caption='[[9c1p]], [[Resolution|resolution]] 2.80Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9c1p]] is a 2 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=9C1P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9C1P 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]] 2.8Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1ATP:(5~{R})-~{N}-[2-(1,2-benzothiazol-3-yl)ethyl]-1-methyl-2,3,4,5-tetrahydro-1-benzazepin-5-amine'>A1ATP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=TRP:TRYPTOPHAN'>TRP</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=9c1p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9c1p OCA], [https://pdbe.org/9c1p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9c1p RCSB], [https://www.ebi.ac.uk/pdbsum/9c1p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9c1p 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 == | ||
| + | Positive allosteric modulator (PAM) drugs enhance the activation of the calcium-sensing receptor (CaSR) and suppress parathyroid hormone (PTH) secretion. Unfortunately, these hyperparathyroidism-treating drugs can induce hypocalcemia and arrhythmias. Seeking improved modulators, we docked libraries of 2.7 million and 1.2 billion molecules against the CaSR structure. The billion-molecule docking found PAMs with a 2.7-fold higher hit rate than the million-molecule library, with hits up to 37-fold more potent. Structure-based optimization led to nanomolar leads. In ex vivo organ assays, one of these PAMs was 100-fold more potent than the standard of care, cinacalcet, and reduced serum PTH levels in mice without the hypocalcemia typical of CaSR drugs. As determined from cryo-electron microscopy structures, the PAMs identified here promote CaSR conformations that more closely resemble the activated state than those induced by the established drugs. | ||
| - | + | Large library docking identifies positive allosteric modulators of the calcium-sensing receptor.,Liu F, Wu CG, Tu CL, Glenn I, Meyerowitz J, Kaplan AL, Lyu J, Cheng Z, Tarkhanova OO, Moroz YS, Irwin JJ, Chang W, Shoichet BK, Skiniotis G Science. 2024 Sep 20;385(6715):eado1868. doi: 10.1126/science.ado1868. Epub 2024 , Sep 20. PMID:39298584<ref>PMID:39298584</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 9c1p" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Skiniotis G]] | ||
| + | [[Category: Wu C]] | ||
Revision as of 04:03, 5 October 2024
Structure of Calcium-Sensing Receptor in complex with positive allosteric modulator '6218
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