A distinct structural mechanism underlies TRPV1 activation by piperine

Yawen Dong, Yue Yin, Simon Vu, Fan Yang, Vladimir Yarov-Yarovoy, Yuhua Tian, Jie Zheng

Research output: Contribution to journalArticle

Abstract

Piperine, the principle pungent compound in black peppers, is known to activate the capsaicin receptor TRPV1 ion channel. How piperine interacts with the channel protein, however, remains unclear. Here we show that piperine binds to the same ligand-binding pocket as capsaicin but in different poses. There was no detectable detrimental effect when T551 and E571, two major sites known to form hydrogen bond with capsaicin, were mutated to a hydrophobic amino acid. Computational structural modeling suggested that piperine makes interactions with multiple amino acids within the ligand binding pocket, including T671 on the pore-forming S6 segment. Mutations of this residue could substantially reduce or even eliminate piperine-induced activation, confirming that T671 is an important site. Our results suggest that the bound piperine may directly interact with the pore-forming S6 segment to induce channel opening. These findings help to explain why piperine is a weak agonist, and may guide future efforts to develop novel pharmaceutical reagents targeting TRPV1.

Original languageEnglish (US)
JournalBiochemical and Biophysical Research Communications
DOIs
StatePublished - Jan 1 2019

Fingerprint

piperine
Chemical activation
S 6
Capsaicin
Piper nigrum
Ligands
TRPV Cation Channels
Amino Acids
Ion Channels
Hydrogen
Hydrogen bonds

Keywords

  • Agonist
  • Capsaicin
  • capsazepine
  • CPZ
  • ECS
  • extracellular solution
  • mouse transient receptor potential cation channel, subfamily V, member 1
  • mTRPV1
  • Nociception
  • Pepper
  • Pungency
  • Spice
  • The abbreviations used are
  • transient receptor potential cation channel, subfamily A, member 1
  • TRPA1
  • van der Waals
  • VDW

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

A distinct structural mechanism underlies TRPV1 activation by piperine. / Dong, Yawen; Yin, Yue; Vu, Simon; Yang, Fan; Yarov-Yarovoy, Vladimir; Tian, Yuhua; Zheng, Jie.

In: Biochemical and Biophysical Research Communications, 01.01.2019.

Research output: Contribution to journalArticle

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abstract = "Piperine, the principle pungent compound in black peppers, is known to activate the capsaicin receptor TRPV1 ion channel. How piperine interacts with the channel protein, however, remains unclear. Here we show that piperine binds to the same ligand-binding pocket as capsaicin but in different poses. There was no detectable detrimental effect when T551 and E571, two major sites known to form hydrogen bond with capsaicin, were mutated to a hydrophobic amino acid. Computational structural modeling suggested that piperine makes interactions with multiple amino acids within the ligand binding pocket, including T671 on the pore-forming S6 segment. Mutations of this residue could substantially reduce or even eliminate piperine-induced activation, confirming that T671 is an important site. Our results suggest that the bound piperine may directly interact with the pore-forming S6 segment to induce channel opening. These findings help to explain why piperine is a weak agonist, and may guide future efforts to develop novel pharmaceutical reagents targeting TRPV1.",
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AU - Vu, Simon

AU - Yang, Fan

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AU - Tian, Yuhua

AU - Zheng, Jie

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