6X2J

Structure of human TRPA1 in complex with agonist GNE551

Summary for 6X2J

• Entry DOI: 10.2210/pdb6x2j/pdb
• EMDB information: 22009
• Descriptor: Transient receptor potential cation channel subfamily A member 1, 5-amino-1-[(4-bromo-2-fluorophenyl)methyl]-N-(2,5-dimethoxyphenyl)-1H-1,2,3-triazole-4-carboxamide (2 entities in total)
• Functional Keywords: trpa1, channel, agonist, membrane protein, membrane protein-agonist complex, membrane protein/agonist
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 292289.55

Authors

Rohou, A.,Rouge, L.,Chen, H. (deposition date: 2020-05-20, release date: 2020-11-18, Last modification date: 2024-03-06)

Primary citation

Liu, C.,Reese, R.,Vu, S.,Rouge, L.,Shields, S.D.,Kakiuchi-Kiyota, S.,Chen, H.,Johnson, K.,Shi, Y.P.,Chernov-Rogan, T.,Greiner, D.M.Z.,Kohli, P.B.,Hackos, D.,Brillantes, B.,Tam, C.,Li, T.,Wang, J.,Safina, B.,Magnuson, S.,Volgraf, M.,Payandeh, J.,Zheng, J.,Rohou, A.,Chen, J.
A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel.
Neuron, 109:273-284.e4, 2021

PubMed Abstract: The TRPA1 ion channel is activated by electrophilic compounds through the covalent modification of intracellular cysteine residues. How non-covalent agonists activate the channel and whether covalent and non-covalent agonists elicit the same physiological responses are not understood. Here, we report the discovery of a non-covalent agonist, GNE551, and determine a cryo-EM structure of the TRPA1-GNE551 complex, revealing a distinct binding pocket and ligand-interaction mechanism. Unlike the covalent agonist allyl isothiocyanate, which elicits channel desensitization, tachyphylaxis, and transient pain, GNE551 activates TRPA1 into a distinct conducting state without desensitization and induces persistent pain. Furthermore, GNE551-evoked pain is relatively insensitive to antagonist treatment. Thus, we demonstrate the biased agonism of TRPA1, a finding that has important implications for the discovery of effective drugs tailored to different disease etiologies.

PubMed: 33152265
DOI: 10.1016/j.neuron.2020.10.014

Experimental method

ELECTRON MICROSCOPY (3 Å)