Rational design and validation of a vanilloid-sensitive TRPV2 ion channel

Fan Yang, Simon Vu, Vladimir Yarov-Yarovoy, Jie Zheng

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Vanilloids activation of TRPV1 represents an excellent model system of ligand-gated ion channels. Recent studies using cryo-electron microcopy (cryo-EM), computational analysis, and functional quantification revealed the location of capsaicin-binding site and critical residues mediating ligand-binding and channel activation. Based on these new findings, here we have successfully introduced high-affinity binding of capsaicin and resiniferatoxin to the vanilloid-insensitive TRPV2 channel, using a rationally designed minimal set of four point mutations (F467S-S498F-L505T-Q525E, termed TRPV2-Quad). We found that binding of resiniferatoxin activates TRPV2-Quad but the ligand-induced open state is relatively unstable, whereas binding of capsaicin to TRPV2-Quad antagonizes resiniferatoxin-induced activation likely through competition for the same binding sites. Using Rosettabased molecular docking, we observed a common structural mechanism underlying vanilloids activation of TRPV1 and TRPV2-Quad, where the ligand serves as molecular "glue" that bridges the S4-S5 linker to the S1-S4 domain to open these channels. Our analysis revealed that capsaicin failed to activate TRPV2-Quad likely due to structural constraints preventing such bridge formation. These results not only validate our current working model for capsaicin activation of TRPV1 but also should help guide the design of drug candidate compounds for this important pain sensor.

Original languageEnglish (US)
Pages (from-to)E3657-E3666
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number26
DOIs
StatePublished - Jun 28 2016

Keywords

  • Capsaicin
  • Ligand gating
  • Resiniferatoxin
  • TRPV1
  • TRPV2

ASJC Scopus subject areas

  • General

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