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6pqo

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Revision as of 23:25, 6 March 2020

Cryo-EM structure of the human TRPA1 ion channel in complex with the covalent agonist JT010

6pqo, resolution 2.88Å

Structural highlights

6pqo is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Experimental data:	Check to display Experimental Data
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 channel subfamily A member 1 (TRPA1) is a Ca(2+)-permeable cation channel that serves as one of the primary sensors of environmental irritants and noxious substances. Many TRPA1 agonists are electrophiles that are recognized by TRPA1 via covalent bond modifications of specific cysteine residues located in the cytoplasmic domains. However, a mechanistic understanding of electrophile sensing by TRPA1 has been limited due to a lack of high-resolution structural information. Here, we present the cryoelectron microscopy (cryo-EM) structures of nanodisc-reconstituted ligand-free TRPA1 and TRPA1 in complex with the covalent agonists JT010 and BITC at 2.8, 2.9, and 3.1 A, respectively. Our structural and functional studies provide the molecular basis for electrophile recognition by the extraordinarily reactive C621 in TRPA1 and mechanistic insights into electrophile-dependent conformational changes in TRPA1. This work also provides a platform for future drug development targeting TRPA1.

Structural Insights into Electrophile Irritant Sensing by the Human TRPA1 Channel.,Suo Y, Wang Z, Zubcevic L, Hsu AL, He Q, Borgnia MJ, Ji RR, Lee SY Neuron. 2019 Dec 6. pii: S0896-6273(19)31009-8. doi:, 10.1016/j.neuron.2019.11.023. PMID:31866091^[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
↑ Suo Y, Wang Z, Zubcevic L, Hsu AL, He Q, Borgnia MJ, Ji RR, Lee SY. Structural Insights into Electrophile Irritant Sensing by the Human TRPA1 Channel. Neuron. 2019 Dec 6. pii: S0896-6273(19)31009-8. doi:, 10.1016/j.neuron.2019.11.023. PMID:31866091 doi:http://dx.doi.org/10.1016/j.neuron.2019.11.023

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6pqo"

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 ==Cryo-EM structure of the human TRPA1 ion channel in complex with the covalent agonist JT010==
-<StructureSection load='6pqo' size='340' side='right'caption='[[6pqo]], [[Resolution|resolution]] 2.88&Aring;' scene=''>
+<SX load='6pqo' size='340' side='right' viewer='molstar' caption='[[6pqo]], [[Resolution|resolution]] 2.88&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[6pqo]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PQO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PQO FirstGlance]. <br>
@@ Line 23: / Line 23: @@
 <references/>
 __TOC__
-</StructureSection>
+</SX>
 [[Category: Large Structures]]
 [[Category: Borgnia, M J]]

6pqo

From Proteopedia

Revision as of 23:25, 6 March 2020

Cryo-EM structure of the human TRPA1 ion channel in complex with the covalent agonist JT010

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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