7d2k

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of rat TRPV6 in complex with (4- phenylcyclohexyl)piperazine inhibitor Br-cis-22a

Structural highlights

7d2k is a 1 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.698Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TRPV6_RAT Calcium selective cation channel probably involved in Ca(2+) uptake in various tissues, including Ca(2+) reabsorption in intestine. The channel is activated by low internal calcium level, probably including intracellular calcium store depletion, and the current exhibits an inward rectification. 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 (By similarity).[UniProtKB:Q91WD2][UniProtKB:Q9H1D0]^[1]

Publication Abstract from PubMed

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.

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Yue L, Peng JB, Hediger MA, Clapham DE. CaT1 manifests the pore properties of the calcium-release-activated calcium channel. Nature. 2001 Apr 5;410(6829):705-9. PMID:11287959 doi:http://dx.doi.org/10.1038/35070596
↑ Bhardwaj R, Lindinger S, Neuberger A, Nadezhdin KD, Singh AK, Cunha MR, Derler I, Gyimesi G, Reymond JL, Hediger MA, Romanin C, Sobolevsky AI. Inactivation-mimicking block of the epithelial calcium channel TRPV6. Sci Adv. 2020 Nov 27;6(48):eabe1508. PMID:33246965 doi:10.1126/sciadv.abe1508

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7d2k"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[7d2k]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7D2K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7D2K FirstGlance]. <br>
-</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=GQC:1-(5-bromanylpyridin-3-yl)-4-[4-(3-methylphenyl)cyclohexyl]piperazin-4-ium'>GQC</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.698&#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=GQC:1-(5-bromanylpyridin-3-yl)-4-[4-(3-methylphenyl)cyclohexyl]piperazin-4-ium'>GQC</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=7d2k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d2k OCA], [https://pdbe.org/7d2k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7d2k RCSB], [https://www.ebi.ac.uk/pdbsum/7d2k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7d2k ProSAT]</span></td></tr>
 </table>
@@ Line 18: / Line 19: @@
 </div>
 <div class="pdbe-citations 7d2k" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Ion channels 3D structures|Ion channels 3D structures]]
 == References ==
 <references/>

7d2k

From Proteopedia

Current revision

Crystal structure of rat TRPV6 in complex with (4- phenylcyclohexyl)piperazine inhibitor Br-cis-22a

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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