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 language | English (US) |
|---|---|
| Journal | Biochemical and Biophysical Research Communications |
| DOIs | |
| State | Published - Jan 1 2019 |
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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 journal › Article
}
TY - JOUR
T1 - A distinct structural mechanism underlies TRPV1 activation by piperine
AU - Dong, Yawen
AU - Yin, Yue
AU - Vu, Simon
AU - Yang, Fan
AU - Yarov-Yarovoy, Vladimir
AU - Tian, Yuhua
AU - Zheng, Jie
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
KW - Agonist
KW - Capsaicin
KW - capsazepine
KW - CPZ
KW - ECS
KW - extracellular solution
KW - mouse transient receptor potential cation channel, subfamily V, member 1
KW - mTRPV1
KW - Nociception
KW - Pepper
KW - Pungency
KW - Spice
KW - The abbreviations used are
KW - transient receptor potential cation channel, subfamily A, member 1
KW - TRPA1
KW - van der Waals
KW - VDW
UR - http://www.scopus.com/inward/record.url?scp=85067233403&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067233403&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2019.06.039
DO - 10.1016/j.bbrc.2019.06.039
M3 - Article
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
ER -