7k4c

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Current revision (05:50, 28 May 2025) (edit) (undo)
 
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<StructureSection load='7k4c' size='340' side='right'caption='[[7k4c]], [[Resolution|resolution]] 3.78&Aring;' scene=''>
<StructureSection load='7k4c' size='340' side='right'caption='[[7k4c]], [[Resolution|resolution]] 3.78&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[7k4c]] is a 4 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=7K4C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7K4C FirstGlance]. <br>
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7K4C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7K4C 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]] 3.78&#8491;</td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.78&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=81F:1-(5-bromopyridin-3-yl)-4-[cis-4-(3-methylphenyl)cyclohexyl]piperazine'>81F</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=81F:1-(5-bromopyridin-3-yl)-4-[cis-4-(3-methylphenyl)cyclohexyl]piperazine'>81F</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</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=7k4c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k4c OCA], [https://pdbe.org/7k4c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k4c RCSB], [https://www.ebi.ac.uk/pdbsum/7k4c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k4c ProSAT]</span></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=7k4c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k4c OCA], [https://pdbe.org/7k4c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k4c RCSB], [https://www.ebi.ac.uk/pdbsum/7k4c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k4c ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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<div style="background-color:#fffaf0;">
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[https://www.uniprot.org/uniprot/TRPV6_HUMAN TRPV6_HUMAN] Calcium selective cation channel that mediates Ca(2+) uptake in various tissues, including the intestine (PubMed:11097838, PubMed:11278579, PubMed:11248124 PubMed:15184369, PubMed:23612980). Important for normal Ca(2+) ion homeostasis in the body, including bone and skin (By similarity). The channel is activated by low internal calcium level, probably including intracellular calcium store depletion, and the current exhibits an inward rectification (PubMed:15184369). Inactivation includes both a rapid Ca(2+)-dependent and a slower Ca(2+)-calmodulin-dependent mechanism; the latter may be regulated by phosphorylation. In vitro, is slowly inhibited by Mg(2+) in a voltage-independent manner. Heteromeric assembly with TRPV5 seems to modify channel properties. TRPV5-TRPV6 heteromultimeric concatemers exhibit voltage-dependent gating.[UniProtKB:Q91WD2]<ref>PMID:11097838</ref> <ref>PMID:11248124</ref> <ref>PMID:11278579</ref> <ref>PMID:15184369</ref> <ref>PMID:23612980</ref>
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== Publication Abstract from PubMed ==
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Epithelial calcium channel TRPV6 plays vital roles in calcium homeostasis, and its dysregulation is implicated in multifactorial diseases, including cancers. Here, we study the molecular mechanism of selective nanomolar-affinity TRPV6 inhibition by (4-phenylcyclohexyl)piperazine derivatives (PCHPDs). We use x-ray crystallography and cryo-electron microscopy to solve the inhibitor-bound structures of TRPV6 and identify two types of inhibitor binding sites in the transmembrane region: (i) modulatory sites between the S1-S4 and pore domains normally occupied by lipids and (ii) the main site in the ion channel pore. Our structural data combined with mutagenesis, functional and computational approaches suggest that PCHPDs plug the open pore of TRPV6 and convert the channel into a nonconducting state, mimicking the action of calmodulin, which causes inactivation of TRPV6 channels under physiological conditions. This mechanism of inhibition explains the high selectivity and potency of PCHPDs and opens up unexplored avenues for the design of future-generation biomimetic drugs.
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Inactivation-mimicking block of the epithelial calcium channel TRPV6.,Bhardwaj R, Lindinger S, Neuberger A, Nadezhdin KD, Singh AK, Cunha MR, Derler I, Gyimesi G, Reymond JL, Hediger MA, Romanin C, Sobolevsky AI Sci Adv. 2020 Nov 27;6(48). pii: 6/48/eabe1508. doi: 10.1126/sciadv.abe1508., Print 2020 Nov. PMID:33246965<ref>PMID:33246965</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7k4c" style="background-color:#fffaf0;"></div>
==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
 
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Nadezhdin KD]]
[[Category: Nadezhdin KD]]

Current revision

Cryo-EM structure of human TRPV6 in complex with (4- phenylcyclohexyl)piperazine inhibitor Br-cis-22a

PDB ID 7k4c

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