6pbe

From Proteopedia

(Difference between revisions)

Revision as of 04:24, 11 April 2020

ZINC17988990-bound TRPV5 in nanodiscs

6pbe, resolution 3.78Å

Structural highlights

6pbe is a 4 chain structure with sequence from European rabbit. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	Trpv5, Ecac1 (European rabbit)
Experimental data:	Check to display Experimental Data
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[TRPV5_RABIT] Constitutively active calcium selective cation channel thought to be involved in Ca(2+) reabsorption in kidney and intestine (PubMed:12574114). Required for normal Ca(2+) reabsorption in the kidney distal convoluted tubules (By similarity). The channel is activated by low internal calcium level and the current exhibits an inward rectification (By similarity). A Ca(2+)-dependent feedback regulation includes fast channel inactivation and slow current decay (By similarity). Heteromeric assembly with TRPV6 seems to modify channel properties. TRPV5-TRPV6 heteromultimeric concatemers exhibit voltage-dependent gating (PubMed:12574114).[UniProtKB:P69744][UniProtKB:Q9NQA5]^[1] ^[2] ^[3]

Publication Abstract from PubMed

Transient receptor potential vanilloid 5 (TRPV5) is a highly calcium selective ion channel that acts as the rate-limiting step of calcium reabsorption in the kidney. The lack of potent, specific modulators of TRPV5 has limited the ability to probe the contribution of TRPV5 in disease phenotypes such as hypercalcemia and nephrolithiasis. Here, we performed structure-based virtual screening (SBVS) at a previously identified TRPV5 inhibitor binding site coupled with electrophysiology screening and identified three novel inhibitors of TRPV5, one of which exhibits high affinity, and specificity for TRPV5 over other TRP channels, including its close homologue TRPV6. Cryo-electron microscopy of TRPV5 in the presence of the specific inhibitor and its parent compound revealed novel binding sites for this channel. Structural and functional analysis have allowed us to suggest a mechanism of action for the selective inhibition of TRPV5 and lay the groundwork for rational design of new classes of TRPV5 modulators.

Structure-based characterization of novel TRPV5 inhibitors.,Hughes TE, Del Rosario JS, Kapoor A, Yazici AT, Yudin Y, Fluck EC, Filizola M, Rohacs T, Moiseenkova-Bell VY Elife. 2019 Oct 24;8. pii: 49572. doi: 10.7554/eLife.49572. PMID:31647410^[4]

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

References

↑ Hoenderop JG, van der Kemp AW, Hartog A, van de Graaf SF, van Os CH, Willems PH, Bindels RJ. Molecular identification of the apical Ca2+ channel in 1, 25-dihydroxyvitamin D3-responsive epithelia. J Biol Chem. 1999 Mar 26;274(13):8375-8. PMID:10085067
↑ Nilius B, Vennekens R, Prenen J, Hoenderop JG, Droogmans G, Bindels RJ. The single pore residue Asp542 determines Ca2+ permeation and Mg2+ block of the epithelial Ca2+ channel. J Biol Chem. 2001 Jan 12;276(2):1020-5. PMID:11035011 doi:http://dx.doi.org/10.1074/jbc.M006184200
↑ Hoenderop JG, Voets T, Hoefs S, Weidema F, Prenen J, Nilius B, Bindels RJ. Homo- and heterotetrameric architecture of the epithelial Ca2+ channels TRPV5 and TRPV6. EMBO J. 2003 Feb 17;22(4):776-85. PMID:12574114 doi:http://dx.doi.org/10.1093/emboj/cdg080
↑ Hughes TE, Del Rosario JS, Kapoor A, Yazici AT, Yudin Y, Fluck EC, Filizola M, Rohacs T, Moiseenkova-Bell VY. Structure-based characterization of novel TRPV5 inhibitors. Elife. 2019 Oct 24;8. pii: 49572. doi: 10.7554/eLife.49572. PMID:31647410 doi:http://dx.doi.org/10.7554/eLife.49572

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6pbe"

@@ Line 3: / Line 3: @@
 <SX load='6pbe' size='340' side='right' viewer='molstar' caption='[[6pbe]], [[Resolution|resolution]] 3.78&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6pbe]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/European_rabbit European rabbit]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PBE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PBE FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6pbe]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/European_rabbit European rabbit]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PBE OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6PBE FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=O6S:(4-oxo-5-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)methyl+3-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propanoate'>O6S</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=O6S:(4-oxo-5-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)methyl+3-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propanoate'>O6S</scene></td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Trpv5, Ecac1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9986 European rabbit])</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6pbe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pbe OCA], [http://pdbe.org/6pbe PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pbe RCSB], [http://www.ebi.ac.uk/pdbsum/6pbe PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pbe ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6pbe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pbe OCA], [http://pdbe.org/6pbe PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pbe RCSB], [http://www.ebi.ac.uk/pdbsum/6pbe PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pbe ProSAT]</span></td></tr>
 </table>
 == Function ==

6pbe

From Proteopedia

Revision as of 04:24, 11 April 2020

ZINC17988990-bound TRPV5 in nanodiscs

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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