Covalent trapping of methyllycaconitine at the α4-α4 interface of the α4α2 nicotinic acetylcholine receptor: Antagonist binding site and mode of receptor inhibition revealed

Nathan L. Absalom; Gracia Quek; Trevor M. Lewis; Taima Qudah; Ida Von Arenstorff; Joseph I. Ambrus; Kasper Harpsøe; Nasiara Karim; Thomas Balle; Malcolm D. McLeod; Mary Chebib

doi:10.1074/jbc.M113.475053

Covalent trapping of methyllycaconitine at the α4-α4 interface of the α4α2 nicotinic acetylcholine receptor: Antagonist binding site and mode of receptor inhibition revealed

Nathan L. Absalom, Gracia Quek, Trevor M. Lewis, Taima Qudah, Ida Von Arenstorff, Joseph I. Ambrus, Kasper Harpsøe, Nasiara Karim, Thomas Balle, Malcolm D. McLeod, Mary Chebib

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

Abstract

Background: Methyllycaconitine is an antagonist at subtypes of the nicotinic acetylcholine receptor. Results: A reactive methyllycaconitine probe was covalently trapped by a cysteine introduced on the complementary face of the α4 subunit and only in the (α4)₃(β2)₂ nAChR stoichiometry. Conclusion: The α4-α4 interface on the α4β2 nAChR contains a methyllycaconitine binding site. Significance: Defining the molecular interactions of nAChR ligands at the α4-α interface may lead to superior therapeutics.

Original language	English
Pages (from-to)	26521-26532
Number of pages	12
Journal	The Journal of Biological Chemistry
Volume	288
Issue number	37
DOIs	https://doi.org/10.1074/jbc.M113.475053
Publication status	Published - 13 Sept 2013
Externally published	Yes

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Absalom, N. L., Quek, G., Lewis, T. M., Qudah, T., Von Arenstorff, I., Ambrus, J. I., Harpsøe, K., Karim, N., Balle, T., McLeod, M. D., & Chebib, M. (2013). Covalent trapping of methyllycaconitine at the α4-α4 interface of the α4α2 nicotinic acetylcholine receptor: Antagonist binding site and mode of receptor inhibition revealed. The Journal of Biological Chemistry, 288(37), 26521-26532. https://doi.org/10.1074/jbc.M113.475053

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title = "Covalent trapping of methyllycaconitine at the α4-α4 interface of the α4α2 nicotinic acetylcholine receptor: Antagonist binding site and mode of receptor inhibition revealed",

abstract = "Background: Methyllycaconitine is an antagonist at subtypes of the nicotinic acetylcholine receptor. Results: A reactive methyllycaconitine probe was covalently trapped by a cysteine introduced on the complementary face of the α4 subunit and only in the (α4)3(β2)2 nAChR stoichiometry. Conclusion: The α4-α4 interface on the α4β2 nAChR contains a methyllycaconitine binding site. Significance: Defining the molecular interactions of nAChR ligands at the α4-α interface may lead to superior therapeutics.",

author = "Absalom, {Nathan L.} and Gracia Quek and Lewis, {Trevor M.} and Taima Qudah and {Von Arenstorff}, Ida and Ambrus, {Joseph I.} and Kasper Harps{\o}e and Nasiara Karim and Thomas Balle and McLeod, {Malcolm D.} and Mary Chebib",

year = "2013",

month = sep,

day = "13",

doi = "10.1074/jbc.M113.475053",

language = "English",

volume = "288",

pages = "26521--26532",

journal = "The Journal of Biological Chemistry",

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Absalom, NL, Quek, G, Lewis, TM, Qudah, T, Von Arenstorff, I, Ambrus, JI, Harpsøe, K, Karim, N, Balle, T, McLeod, MD & Chebib, M 2013, 'Covalent trapping of methyllycaconitine at the α4-α4 interface of the α4α2 nicotinic acetylcholine receptor: Antagonist binding site and mode of receptor inhibition revealed', The Journal of Biological Chemistry, vol. 288, no. 37, pp. 26521-26532. https://doi.org/10.1074/jbc.M113.475053

Covalent trapping of methyllycaconitine at the α4-α4 interface of the α4α2 nicotinic acetylcholine receptor: Antagonist binding site and mode of receptor inhibition revealed. / Absalom, Nathan L.; Quek, Gracia; Lewis, Trevor M. et al.
In: The Journal of Biological Chemistry, Vol. 288, No. 37, 13.09.2013, p. 26521-26532.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Covalent trapping of methyllycaconitine at the α4-α4 interface of the α4α2 nicotinic acetylcholine receptor

T2 - Antagonist binding site and mode of receptor inhibition revealed

AU - Absalom, Nathan L.

AU - Quek, Gracia

AU - Lewis, Trevor M.

AU - Qudah, Taima

AU - Von Arenstorff, Ida

AU - Ambrus, Joseph I.

AU - Harpsøe, Kasper

AU - Karim, Nasiara

AU - Balle, Thomas

AU - McLeod, Malcolm D.

AU - Chebib, Mary

PY - 2013/9/13

Y1 - 2013/9/13

N2 - Background: Methyllycaconitine is an antagonist at subtypes of the nicotinic acetylcholine receptor. Results: A reactive methyllycaconitine probe was covalently trapped by a cysteine introduced on the complementary face of the α4 subunit and only in the (α4)3(β2)2 nAChR stoichiometry. Conclusion: The α4-α4 interface on the α4β2 nAChR contains a methyllycaconitine binding site. Significance: Defining the molecular interactions of nAChR ligands at the α4-α interface may lead to superior therapeutics.

AB - Background: Methyllycaconitine is an antagonist at subtypes of the nicotinic acetylcholine receptor. Results: A reactive methyllycaconitine probe was covalently trapped by a cysteine introduced on the complementary face of the α4 subunit and only in the (α4)3(β2)2 nAChR stoichiometry. Conclusion: The α4-α4 interface on the α4β2 nAChR contains a methyllycaconitine binding site. Significance: Defining the molecular interactions of nAChR ligands at the α4-α interface may lead to superior therapeutics.

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SN - 0021-9258

VL - 288

SP - 26521

EP - 26532

JO - The Journal of Biological Chemistry

JF - The Journal of Biological Chemistry

IS - 37

ER -

Covalent trapping of methyllycaconitine at the α4-α4 interface of the α4α2 nicotinic acetylcholine receptor: Antagonist binding site and mode of receptor inhibition revealed

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