| Structural highlights
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
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