7jup

Structure of human TRPA1 in complex with antagonist compound 21Structure of human TRPA1 in complex with antagonist compound 21

Structural highlights

7jup is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	TRPA1, ANKTM1 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[TRPA1_HUMAN] Familial episodic pain syndrome with predominantly upper body involvement. The disease is caused by mutations affecting the gene represented in this entry.

Function

[TRPA1_HUMAN] Receptor-activated non-selective cation channel involved in detection of pain and possibly also in cold perception and inner ear function (PubMed:25389312, PubMed:25855297). Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of volatile irritants, such as mustard oil, cinnamaldehyde, garlic and acrolein, an irritant from tears gas and vehicule exhaust fumes (PubMed:25389312, PubMed:20547126). Is also activated by menthol (in vitro)(PubMed:25389312). Acts also as an ionotropic cannabinoid receptor by being activated by delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana (PubMed:25389312). May be a component for the mechanosensitive transduction channel of hair cells in inner ear, thereby participating in the perception of sounds. Probably operated by a phosphatidylinositol second messenger system (By similarity).[UniProtKB:Q8BLA8]^[1] ^[2] ^[3]

Publication Abstract from PubMed

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium-permeable ion channel highly expressed in the primary sensory neurons functioning as a polymodal sensor for exogenous and endogenous stimuli and has generated widespread interest as a target for inhibition due to its implication in neuropathic pain and respiratory disease. Herein, we describe the optimization of a series of potent, selective, and orally bioavailable TRPA1 small molecule antagonists, leading to the discovery of a novel tetrahydrofuran-based linker. Given the balance of physicochemical properties and strong in vivo target engagement in a rat AITC-induced pain assay, compound 20 was progressed into a guinea pig ovalbumin asthma model where it exhibited significant dose-dependent reduction of inflammatory response. Furthermore, the structure of the TRPA1 channel bound to compound 21 was determined via cryogenic electron microscopy to a resolution of 3 A, revealing the binding site and mechanism of action for this class of antagonists.

Tetrahydrofuran-Based Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists: Ligand-Based Discovery, Activity in a Rodent Asthma Model, and Mechanism-of-Action via Cryogenic Electron Microscopy.,Terrett JA, Chen H, Shore DG, Villemure E, Larouche-Gauthier R, Dery M, Beaumier F, Constantineau-Forget L, Grand-Maitre C, Lepissier L, Ciblat S, Sturino C, Chen Y, Hu B, Lu A, Wang Y, Cridland AP, Ward SI, Hackos DH, Reese RM, Shields SD, Chen J, Balestrini A, Riol-Blanco L, Lee WP, Liu J, Suto E, Wu X, Zhang J, Ly JQ, La H, Johnson K, Baumgardner M, Chou KJ, Rohou A, Rouge L, Safina BS, Magnuson S, Volgraf M J Med Chem. 2021 Mar 22. doi: 10.1021/acs.jmedchem.0c02023. PMID:33749283^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kremeyer B, Lopera F, Cox JJ, Momin A, Rugiero F, Marsh S, Woods CG, Jones NG, Paterson KJ, Fricker FR, Villegas A, Acosta N, Pineda-Trujillo NG, Ramirez JD, Zea J, Burley MW, Bedoya G, Bennett DL, Wood JN, Ruiz-Linares A. A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron. 2010 Jun 10;66(5):671-80. doi: 10.1016/j.neuron.2010.04.030. PMID:20547126 doi:http://dx.doi.org/10.1016/j.neuron.2010.04.030
↑ Moparthi L, Survery S, Kreir M, Simonsen C, Kjellbom P, Hogestatt ED, Johanson U, Zygmunt PM. Human TRPA1 is intrinsically cold- and chemosensitive with and without its N-terminal ankyrin repeat domain. Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16901-6. doi:, 10.1073/pnas.1412689111. Epub 2014 Nov 11. PMID:25389312 doi:http://dx.doi.org/10.1073/pnas.1412689111
↑ Paulsen CE, Armache JP, Gao Y, Cheng Y, Julius D. Structure of the TRPA1 ion channel suggests regulatory mechanisms. Nature. 2015 Apr 8. doi: 10.1038/nature14367. PMID:25855297 doi:http://dx.doi.org/10.1038/nature14367
↑ Terrett JA, Chen H, Shore DG, Villemure E, Larouche-Gauthier R, Dery M, Beaumier F, Constantineau-Forget L, Grand-Maitre C, Lepissier L, Ciblat S, Sturino C, Chen Y, Hu B, Lu A, Wang Y, Cridland AP, Ward SI, Hackos DH, Reese RM, Shields SD, Chen J, Balestrini A, Riol-Blanco L, Lee WP, Liu J, Suto E, Wu X, Zhang J, Ly JQ, La H, Johnson K, Baumgardner M, Chou KJ, Rohou A, Rouge L, Safina BS, Magnuson S, Volgraf M. Tetrahydrofuran-Based Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists: Ligand-Based Discovery, Activity in a Rodent Asthma Model, and Mechanism-of-Action via Cryogenic Electron Microscopy. J Med Chem. 2021 Mar 22. doi: 10.1021/acs.jmedchem.0c02023. PMID:33749283 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c02023

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OCA

[1] Kremeyer B, Lopera F, Cox JJ, Momin A, Rugiero F, Marsh S, Woods CG, Jones NG, Paterson KJ, Fricker FR, Villegas A, Acosta N, Pineda-Trujillo NG, Ramirez JD, Zea J, Burley MW, Bedoya G, Bennett DL, Wood JN, Ruiz-Linares A. A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron. 2010 Jun 10;66(5):671-80. doi: 10.1016/j.neuron.2010.04.030. PMID:20547126 doi:http://dx.doi.org/10.1016/j.neuron.2010.04.030

[2] Moparthi L, Survery S, Kreir M, Simonsen C, Kjellbom P, Hogestatt ED, Johanson U, Zygmunt PM. Human TRPA1 is intrinsically cold- and chemosensitive with and without its N-terminal ankyrin repeat domain. Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16901-6. doi:, 10.1073/pnas.1412689111. Epub 2014 Nov 11. PMID:25389312 doi:http://dx.doi.org/10.1073/pnas.1412689111

[3] Paulsen CE, Armache JP, Gao Y, Cheng Y, Julius D. Structure of the TRPA1 ion channel suggests regulatory mechanisms. Nature. 2015 Apr 8. doi: 10.1038/nature14367. PMID:25855297 doi:http://dx.doi.org/10.1038/nature14367

[4] Terrett JA, Chen H, Shore DG, Villemure E, Larouche-Gauthier R, Dery M, Beaumier F, Constantineau-Forget L, Grand-Maitre C, Lepissier L, Ciblat S, Sturino C, Chen Y, Hu B, Lu A, Wang Y, Cridland AP, Ward SI, Hackos DH, Reese RM, Shields SD, Chen J, Balestrini A, Riol-Blanco L, Lee WP, Liu J, Suto E, Wu X, Zhang J, Ly JQ, La H, Johnson K, Baumgardner M, Chou KJ, Rohou A, Rouge L, Safina BS, Magnuson S, Volgraf M. Tetrahydrofuran-Based Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists: Ligand-Based Discovery, Activity in a Rodent Asthma Model, and Mechanism-of-Action via Cryogenic Electron Microscopy. J Med Chem. 2021 Mar 22. doi: 10.1021/acs.jmedchem.0c02023. PMID:33749283 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c02023

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