TRPA1 ankyrin repeat six interacts with a small molecule inhibitor chemotype
Autor: | Brett Antonio, Katrina E. Yoger, David C. Pryde, Aaron C. Gerlach, Seungil Han, Wei Chou Tseng, Veerabahu Shanmugasundaram, Karen M. Padilla |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Models Molecular Mutagenesis (molecular biology technique) Small Molecule Libraries 03 medical and health sciences Transient receptor potential channel Animals Humans Amino Acid Sequence TRPA1 Cation Channel Ion channel chemistry.chemical_classification Multidisciplinary food and beverages Biological Sciences Small molecule Amino acid Ankyrin Repeat Rats Transmembrane domain 030104 developmental biology chemistry Biochemistry Lipophilicity Ankyrin repeat Sequence Alignment psychological phenomena and processes Protein Binding |
Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 115(48) |
ISSN: | 1091-6490 |
Popis: | TRPA1, a member of the transient receptor potential channel (TRP) family, is genetically linked to pain in humans, and small molecule inhibitors are efficacious in preclinical animal models of inflammatory pain. These findings have driven significant interest in development of selective TRPA1 inhibitors as potential analgesics. The majority of TRPA1 inhibitors characterized to date have been reported to interact with the S5 transmembrane helices forming part of the pore region of the channel. However, the development of many of these inhibitors as clinical drug candidates has been prevented by high lipophilicity, low solubility, and poor pharmacokinetic profiles. Identification of alternate compound interacting sites on TRPA1 provides the opportunity to develop structurally distinct modulators with novel structure-activity relationships and more desirable physiochemical properties. In this paper, we have identified a previously undescribed potent and selective small molecule thiadiazole structural class of TRPA1 inhibitor. Using species ortholog chimeric and mutagenesis strategies, we narrowed down the site of interaction to ankyrinR #6 within the distal N-terminal region of TRPA1. To identify the individual amino acid residues involved, we generated a computational model of the ankyrinR domain. This model was used predictively to identify three critical amino acids in human TRPA1, G238, N249, and K270, which were confirmed by mutagenesis to account for compound activity. These findings establish a small molecule interaction region on TRPA1, expanding potential avenues for developing TRPA1 inhibitor analgesics and for probing the mechanism of channel gating. |
Databáze: | OpenAIRE |
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