6d7t

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Cryo-EM structure of human TRPV6-Y467A in complex with 2-Aminoethoxydiphenyl borate (2-APB)

Structural highlights

6d7t is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 4.44Å
Experimental data:Check to display Experimental Data
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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][1] [2] [3] [4] [5]

Publication Abstract from PubMed

Transient receptor potential (TRP) channels are involved in various physiological processes, including sensory transduction. The TRP channel TRPV6 mediates calcium uptake in epithelia and its expression is dramatically increased in numerous types of cancer. TRPV6 inhibitors suppress tumor growth, but the molecular mechanism of inhibition remains unknown. Here, we present crystal and cryo-EM structures of human and rat TRPV6 bound to 2-aminoethoxydiphenyl borate (2-APB), a TRPV6 inhibitor and modulator of numerous TRP channels. 2-APB binds to TRPV6 in a pocket formed by the cytoplasmic half of the S1-S4 transmembrane helix bundle. Comparing human wild-type and high-affinity mutant Y467A structures, we show that 2-APB induces TRPV6 channel closure by modulating protein-lipid interactions. Mutagenesis and functional analyses suggest that the identified 2-APB binding site might be present in other members of vanilloid subfamily TRP channels. Our findings reveal a mechanism of ion channel allosteric modulation that can be exploited for therapeutic design.

Structural bases of TRP channel TRPV6 allosteric modulation by 2-APB.,Singh AK, Saotome K, McGoldrick LL, Sobolevsky AI Nat Commun. 2018 Jun 25;9(1):2465. doi: 10.1038/s41467-018-04828-y. PMID:29941865[6]

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

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See Also

References

  1. ↑ Peng JB, Chen XZ, Berger UV, Weremowicz S, Morton CC, Vassilev PM, Brown EM, Hediger MA. Human calcium transport protein CaT1. Biochem Biophys Res Commun. 2000 Nov 19;278(2):326-32. doi:, 10.1006/bbrc.2000.3716. PMID:11097838 doi:http://dx.doi.org/10.1006/bbrc.2000.3716
  2. ↑ Niemeyer BA, Bergs C, Wissenbach U, Flockerzi V, Trost C. Competitive regulation of CaT-like-mediated Ca2+ entry by protein kinase C and calmodulin. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3600-5. doi: 10.1073/pnas.051511398. PMID:11248124 doi:http://dx.doi.org/10.1073/pnas.051511398
  3. ↑ Wissenbach U, Niemeyer BA, Fixemer T, Schneidewind A, Trost C, Cavalie A, Reus K, Meese E, Bonkhoff H, Flockerzi V. Expression of CaT-like, a novel calcium-selective channel, correlates with the malignancy of prostate cancer. J Biol Chem. 2001 Jun 1;276(22):19461-8. doi: 10.1074/jbc.M009895200. Epub 2001, Feb 2. PMID:11278579 doi:http://dx.doi.org/10.1074/jbc.M009895200
  4. ↑ Bodding M, Flockerzi V. Ca2+ dependence of the Ca2+-selective TRPV6 channel. J Biol Chem. 2004 Aug 27;279(35):36546-52. doi: 10.1074/jbc.M404679200. Epub 2004, Jun 7. PMID:15184369 doi:http://dx.doi.org/10.1074/jbc.M404679200
  5. ↑ Fecher-Trost C, Wissenbach U, Beck A, Schalkowsky P, Stoerger C, Doerr J, Dembek A, Simon-Thomas M, Weber A, Wollenberg P, Ruppert T, Middendorff R, Maurer HH, Flockerzi V. The in vivo TRPV6 protein starts at a non-AUG triplet, decoded as methionine, upstream of canonical initiation at AUG. J Biol Chem. 2013 Jun 7;288(23):16629-44. doi: 10.1074/jbc.M113.469726. Epub 2013, Apr 23. PMID:23612980 doi:http://dx.doi.org/10.1074/jbc.M113.469726
  6. ↑ Singh AK, Saotome K, McGoldrick LL, Sobolevsky AI. Structural bases of TRP channel TRPV6 allosteric modulation by 2-APB. Nat Commun. 2018 Jun 25;9(1):2465. doi: 10.1038/s41467-018-04828-y. PMID:29941865 doi:http://dx.doi.org/10.1038/s41467-018-04828-y

Contents


6d7t, resolution 4.44Å

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