Molecular dynamics simulations of dihydro-β-erythroidine bound to the human α4β2 nicotinic acetylcholine receptor.
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
11
11
2018
revised:
20
03
2019
accepted:
10
04
2019
pubmed:
8
5
2019
medline:
12
9
2020
entrez:
8
5
2019
Statut:
ppublish
Résumé
The heteromeric α4β2 nicotinic acetylcholine receptor (nAChR) is abundant in the human brain and is associated with a range of CNS disorders. This nAChR subtype has been recently crystallised in a conformation that was proposed to represent a desensitised state. Here, we investigated the conformational transition mechanism of this nAChR from a desensitised to a closed/resting state. The competitive antagonist dihydro-β-erythroidine (DHβE) was modelled by replacement of the agonist nicotine in the α4β2 nAChR experimental structure. DHβE is used both in vitro and in vivo for its ability to block α4β2 nAChRs. This system was studied by three molecular dynamics simulations with a combined simulation time of 2.6 μs. Electrophysiological studies of mutated receptors were performed to validate the simulation results. The relative positions of the extracellular and transmembrane domains in the models are distinct from those of the desensitised state structure and are compatible with experimental structures of Cys-loop receptors captured in a closed/resting state. Our model suggests that the side chains of α4 L257 (9') and α4 L264 (16') are the main constrictions in the transmembrane pore. The involvement of position 9' in channel gating is well established, but position 16' was only previously identified as a gate for the bacterial channels, ELIC and GLIC. L257 but not L264 was found to influence the slow component of desensitisation. The structure of the antagonist-bound state proposed here should be valuable for the development of therapeutic or insecticide compounds.
Sections du résumé
BACKGROUND AND PURPOSE
The heteromeric α4β2 nicotinic acetylcholine receptor (nAChR) is abundant in the human brain and is associated with a range of CNS disorders. This nAChR subtype has been recently crystallised in a conformation that was proposed to represent a desensitised state. Here, we investigated the conformational transition mechanism of this nAChR from a desensitised to a closed/resting state.
EXPERIMENTAL APPROACH
The competitive antagonist dihydro-β-erythroidine (DHβE) was modelled by replacement of the agonist nicotine in the α4β2 nAChR experimental structure. DHβE is used both in vitro and in vivo for its ability to block α4β2 nAChRs. This system was studied by three molecular dynamics simulations with a combined simulation time of 2.6 μs. Electrophysiological studies of mutated receptors were performed to validate the simulation results.
KEY RESULTS
The relative positions of the extracellular and transmembrane domains in the models are distinct from those of the desensitised state structure and are compatible with experimental structures of Cys-loop receptors captured in a closed/resting state.
CONCLUSIONS AND IMPLICATIONS
Our model suggests that the side chains of α4 L257 (9') and α4 L264 (16') are the main constrictions in the transmembrane pore. The involvement of position 9' in channel gating is well established, but position 16' was only previously identified as a gate for the bacterial channels, ELIC and GLIC. L257 but not L264 was found to influence the slow component of desensitisation. The structure of the antagonist-bound state proposed here should be valuable for the development of therapeutic or insecticide compounds.
Identifiants
pubmed: 31062355
doi: 10.1111/bph.14698
pmc: PMC6609542
doi:
Substances chimiques
Nicotinic Antagonists
0
Receptors, Nicotinic
0
nicotinic receptor alpha4beta2
0
Dihydro-beta-Erythroidine
23255-54-1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2750-2763Informations de copyright
© 2019 The British Pharmacological Society.
Références
Protein Sci. 2018 Jan;27(1):293-315
pubmed: 29067766
Nature. 2014 Aug 21;512(7514):270-5
pubmed: 24909990
Biochemistry. 1980 Nov 11;19(23):5344-53
pubmed: 7448173
Nature. 2016 Oct 20;538(7625):411-415
pubmed: 27698419
J Chem Theory Comput. 2016 Jan 12;12(1):405-13
pubmed: 26631602
Nucleic Acids Res. 2018 Jan 4;46(D1):D1091-D1106
pubmed: 29149325
J Chem Theory Comput. 2014 Feb 11;10(2):865-879
pubmed: 24803855
Trends Pharmacol Sci. 2015 Feb;36(2):96-108
pubmed: 25639674
Br J Pharmacol. 2017 Dec;174 Suppl 1:S130-S159
pubmed: 29055038
J Chem Inf Model. 2018 Nov 26;58(11):2278-2293
pubmed: 30359518
J Gen Physiol. 2013 Apr;141(4):467-78
pubmed: 23478996
Nature. 2004 Aug 19;430(7002):896-900
pubmed: 15318223
J Biol Chem. 2012 Nov 23;287(48):40207-15
pubmed: 23038257
J Gen Physiol. 2017 Jan;149(1):85-103
pubmed: 27932572
J Comput Chem. 2005 Dec;26(16):1668-88
pubmed: 16200636
J Comput Chem. 2004 Jul 15;25(9):1157-74
pubmed: 15116359
J Comput Chem. 2011 Jul 30;32(10):2319-27
pubmed: 21500218
J Mol Model. 2017 Sep;23(9):251
pubmed: 28770361
J Mol Graph. 1996 Dec;14(6):354-60, 376
pubmed: 9195488
J Neurobiol. 2002 Dec;53(4):457-78
pubmed: 12436413
J Physiol Paris. 2012 Jan;106(1-2):23-33
pubmed: 21995938
J Chem Theory Comput. 2015 Aug 11;11(8):3696-713
pubmed: 26574453
Nature. 1991 Oct 31;353(6347):846-9
pubmed: 1719423
J Mol Biol. 2005 Mar 4;346(4):967-89
pubmed: 15701510
J Chem Theory Comput. 2013 Feb 12;9(2):909-26
pubmed: 26588735
Br J Pharmacol. 2019 Aug;176(15):2750-2763
pubmed: 31062355
Nature. 2015 Oct 8;526(7572):224-9
pubmed: 26344198
Nature. 2001 May 17;411(6835):269-76
pubmed: 11357122
Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1261-5
pubmed: 1741378
J Mol Biol. 2008 Aug 29;381(2):478-86
pubmed: 18585736
Structure. 2013 Aug 6;21(8):1271-83
pubmed: 23931140
PLoS Comput Biol. 2008 Jan;4(1):e19
pubmed: 18225945
Neuropharmacology. 2015 Sep;96(Pt B):137-49
pubmed: 25529272
J Pestic Sci. 2017 Aug 20;42(3):67-83
pubmed: 30363948
FEBS Lett. 1982 Mar 22;139(2):225-9
pubmed: 7075777
Nat Struct Mol Biol. 2016 Jun 7;23(6):494-502
pubmed: 27273633
Psychopharmacology (Berl). 2018 Sep;235(9):2479-2505
pubmed: 29980822
Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):E3987-96
pubmed: 24043807
Basic Clin Pharmacol Toxicol. 2015 Mar;116(3):187-200
pubmed: 25441336
Neuron. 2016 May 4;90(3):452-70
pubmed: 27151638
Basic Clin Pharmacol Toxicol. 2016 Jun;118(6):399-407
pubmed: 26572235
FEBS Lett. 1973 Dec 15;38(1):11-5
pubmed: 4772687
Nature. 2018 May;557(7704):261-265
pubmed: 29720657
PLoS One. 2012;7(8):e40757
pubmed: 22927902