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Inactivation-mimicking block of the epithelial calcium channel TRPV6.

Authors
  • Bhardwaj, Rajesh1
  • Lindinger, Sonja2
  • Neuberger, Arthur3
  • Nadezhdin, Kirill D3
  • Singh, Appu K3, 4
  • Cunha, Micael R5
  • Derler, Isabella2
  • Gyimesi, Gergely1
  • Reymond, Jean-Louis5
  • Hediger, Matthias A6
  • Romanin, Christoph7
  • Sobolevsky, Alexander I8
  • 1 Department of Nephrology and Hypertension and Department of Biomedical Research, University of Bern, Inselspital, Freiburgstrasse 15, CH-3010 Bern, Switzerland. , (Switzerland)
  • 2 Institute of Biophysics, Johannes Kepler University Linz, Gruberstrasse 40, 4020 Linz, Austria. , (Austria)
  • 3 Department of Biochemistry and Molecular Biophysics, Columbia University, 650 West 168th Street, New York, NY 10032, USA.
  • 4 Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India. , (India)
  • 5 Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland. , (Switzerland)
  • 6 Department of Nephrology and Hypertension and Department of Biomedical Research, University of Bern, Inselspital, Freiburgstrasse 15, CH-3010 Bern, Switzerland. [email protected] [email protected] [email protected] , (Switzerland)
  • 7 Institute of Biophysics, Johannes Kepler University Linz, Gruberstrasse 40, 4020 Linz, Austria. [email protected] [email protected] [email protected] , (Austria)
  • 8 Department of Biochemistry and Molecular Biophysics, Columbia University, 650 West 168th Street, New York, NY 10032, USA. [email protected] [email protected] [email protected] , (Oman)
Type
Published Article
Journal
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Publication Date
Nov 01, 2020
Volume
6
Issue
48
Identifiers
DOI: 10.1126/sciadv.abe1508
PMID: 33246965
Source
Medline
Language
English
License
Unknown

Abstract

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. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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