A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel.
TRPA1
biased agonism
covalent
cryo-EM
drug discovery
ion channel
non-covalent
pain
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
20 01 2021
20 01 2021
Historique:
received:
23
06
2020
revised:
31
08
2020
accepted:
09
10
2020
pubmed:
6
11
2020
medline:
18
2
2021
entrez:
5
11
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33152265
pii: S0896-6273(20)30810-2
doi: 10.1016/j.neuron.2020.10.014
pmc: PMC8244166
mid: NIHMS1645330
pii:
doi:
Substances chimiques
Ligands
0
TRPA1 Cation Channel
0
Trpa1 protein, rat
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
273-284.e4Subventions
Organisme : NINDS NIH HHS
ID : R01 NS103954
Pays : United States
Organisme : NIGMS NIH HHS
ID : U24 GM129547
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests All of the authors, except S.V. and J.Z., are current or former employees of Genentech, a member of the Roche group, and may hold Roche stock or stock options.
Références
J Med Chem. 2018 Apr 26;61(8):3641-3659
pubmed: 29590749
Nat Commun. 2013;4:2501
pubmed: 24071625
Nat Chem Biol. 2015 Jul;11(7):518-524
pubmed: 26053297
Nature. 2016 May 18;534(7607):347-51
pubmed: 27281200
Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19564-8
pubmed: 17164327
Protein Sci. 2021 Jan;30(1):70-82
pubmed: 32881101
Mol Pain. 2016 Nov 29;12:
pubmed: 27899696
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
J Struct Biol. 2005 Oct;152(1):36-51
pubmed: 16182563
Acta Crystallogr D Struct Biol. 2018 Jun 1;74(Pt 6):519-530
pubmed: 29872003
Nat Methods. 2020 Sep;17(9):923-927
pubmed: 32807957
Pain. 2017 Sep;158(9):1723-1732
pubmed: 28614189
Neuron. 2020 Mar 4;105(5):882-894.e5
pubmed: 31866091
Nature. 2020 Sep;585(7823):141-145
pubmed: 32641835
Channels (Austin). 2008 Jul-Aug;2(4):287-98
pubmed: 18769139
Cell. 2006 Mar 24;124(6):1269-82
pubmed: 16564016
J Neurosci. 2019 May 15;39(20):3845-3855
pubmed: 30862667
Science. 2019 Mar 1;363(6430):
pubmed: 30733385
Cell. 2003 Mar 21;112(6):819-29
pubmed: 12654248
Proc Natl Acad Sci U S A. 2016 Jan 12;113(2):E137-45
pubmed: 26719417
Nat Struct Mol Biol. 2018 Jan;25(1):53-60
pubmed: 29323279
Cell. 2019 Dec 12;179(7):1582-1589.e7
pubmed: 31787376
Physiol Rev. 2020 Apr 1;100(2):725-803
pubmed: 31670612
Elife. 2018 Mar 07;7:
pubmed: 29513216
Nat Neurosci. 2006 May;9(5):628-35
pubmed: 16617338
J Neurophysiol. 2019 Feb 1;121(2):427-443
pubmed: 30485151
Sci Rep. 2020 Jan 22;10(1):979
pubmed: 31969645
Nat Rev Drug Discov. 2017 Jan;16(1):19-34
pubmed: 27910877
Naunyn Schmiedebergs Arch Pharmacol. 2015 Apr;388(4):451-63
pubmed: 25640188
Neuron. 2004 Mar 25;41(6):849-57
pubmed: 15046718
J Neurosci. 2007 Sep 12;27(37):9874-84
pubmed: 17855602
Acta Crystallogr D Struct Biol. 2018 Jun 1;74(Pt 6):531-544
pubmed: 29872004
Neuron. 2006 Apr 20;50(2):277-89
pubmed: 16630838
Science. 2019 Sep 27;365(6460):1434-1440
pubmed: 31488702
Circulation. 2018 May 29;137(22):2315-2317
pubmed: 29844068
Anal Chem. 2015 Apr 7;87(7):3646-54
pubmed: 25774910
Nature. 2004 Jan 15;427(6971):260-5
pubmed: 14712238
J Neurosci. 2008 May 7;28(19):5063-71
pubmed: 18463259
Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):9099-104
pubmed: 19458046
Structure. 2020 Feb 4;28(2):169-184.e5
pubmed: 31806353
Nature. 2007 Feb 1;445(7127):541-5
pubmed: 17237762
Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):3762-3767
pubmed: 28320952
Biochemistry. 1998 Oct 20;37(42):14713-8
pubmed: 9778346
Annu Rev Physiol. 2013;75:181-200
pubmed: 23020579
J Biol Chem. 1998 Jan 30;273(5):3097-104
pubmed: 9446627
J Neurosci. 2008 Sep 24;28(39):9640-51
pubmed: 18815250
Nat Chem Biol. 2020 Feb;16(2):188-196
pubmed: 31959964
Pflugers Arch. 2008 Oct;457(1):77-89
pubmed: 18461353
Neuron. 2010 Jun 10;66(5):671-80
pubmed: 20547126
Pain. 2011 May;152(5):1165-1172
pubmed: 21402443
J Exp Med. 1938 Sep 30;68(4):505-12
pubmed: 19870801
J Struct Biol. 2013 Nov;184(2):226-36
pubmed: 23954653
Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):26008-26019
pubmed: 31796582
Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13519-24
pubmed: 17684094
Elife. 2019 Jun 11;8:
pubmed: 31184584
Cell. 2019 Sep 5;178(6):1362-1374.e16
pubmed: 31447178
J Neurosci. 2013 May 29;33(22):9283-94
pubmed: 23719797
Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6721-6
pubmed: 22493235
Elife. 2019 May 15;8:
pubmed: 31090543
Nature. 2015 Sep 24;525(7570):552
pubmed: 26200340