TY - JOUR
T1 - Structural mechanisms underlying activation of TRPV1 channels by pungent compounds in gingers
AU - Yin, Yue
AU - Dong, Yawen
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 - Background and Purpose: Like chili peppers, gingers produce pungent stimuli by a group of vanilloid compounds that activate the nociceptive transient receptor potential vanilloid 1 (TRPV1) ion channel. How these compounds interact with TRPV1 remains unclear. Experimental Approach: We used computational structural modelling, functional tests (electrophysiology and calcium imaging), and mutagenesis to investigate the structural mechanisms underlying ligand–channel interactions. Key Results: The potency of three principal pungent compounds from ginger —shogaol, gingerol, and zingerone—depends on the same two residues in the TRPV1 channel that form a hydrogen bond with the chili pepper pungent compound, capsaicin. Computational modelling revealed binding poses of these ginger compounds similar to those of capsaicin, including a “head-down tail-up” orientation, two specific hydrogen bonds, and important contributions of van der Waals interactions by the aliphatic tail. Our study also identified a novel horizontal binding pose of zingerone that allows it to directly interact with the channel pore when bound inside the ligand-binding pocket. These observations offer a molecular level explanation for how unique structures in the ginger compounds affect their channel activation potency. Conclusions and Implications: Mechanistic insights into the interactions of ginger compounds and the TRPV1 cation channel should help guide drug discovery efforts to modulate nociception.
AB - Background and Purpose: Like chili peppers, gingers produce pungent stimuli by a group of vanilloid compounds that activate the nociceptive transient receptor potential vanilloid 1 (TRPV1) ion channel. How these compounds interact with TRPV1 remains unclear. Experimental Approach: We used computational structural modelling, functional tests (electrophysiology and calcium imaging), and mutagenesis to investigate the structural mechanisms underlying ligand–channel interactions. Key Results: The potency of three principal pungent compounds from ginger —shogaol, gingerol, and zingerone—depends on the same two residues in the TRPV1 channel that form a hydrogen bond with the chili pepper pungent compound, capsaicin. Computational modelling revealed binding poses of these ginger compounds similar to those of capsaicin, including a “head-down tail-up” orientation, two specific hydrogen bonds, and important contributions of van der Waals interactions by the aliphatic tail. Our study also identified a novel horizontal binding pose of zingerone that allows it to directly interact with the channel pore when bound inside the ligand-binding pocket. These observations offer a molecular level explanation for how unique structures in the ginger compounds affect their channel activation potency. Conclusions and Implications: Mechanistic insights into the interactions of ginger compounds and the TRPV1 cation channel should help guide drug discovery efforts to modulate nociception.
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U2 - 10.1111/bph.14766
DO - 10.1111/bph.14766
M3 - Article
C2 - 31207668
AN - SCOPUS:85069946216
VL - 176
SP - 3364
EP - 3377
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 17
ER -