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Probing for and Quantifying Agonist Hydrogen Bonds in α6β2 Nicotinic Acetylcholine Receptors

Post, Michael R. and Lester, Henry A. and Dougherty, Dennis A. (2017) Probing for and Quantifying Agonist Hydrogen Bonds in α6β2 Nicotinic Acetylcholine Receptors. Biochemistry, 56 (13). pp. 1836-1840. ISSN 0006-2960. PMCID PMC6075822. doi:10.1021/acs.biochem.7b00213.

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Designing subtype-selective agonists for neuronal nicotinic acetylcholine receptors (nACh¬R) is a challenging and significant goal aided by intricate knowledge of each subtype’s binding patterns. We previously reported that in α6β2 receptors, acetylcholine makes a functional cation-π interaction with Trp149, but nicotine and TC299423 do not, suggesting a distinctive binding site. This work explores hydrogen binding at the backbone carbonyl associated with α6β2 Trp149. Substituting the i+1 residue, Thr150, with its α-hydroxy analogue (Tah) attenuates the carbonyl’s hydrogen bond accepting ability. At α6(T150Tah)β2, nicotine shows a 24-fold loss of function, TC299423 shows a modest loss, and acetylcholine shows no effect. Nicotine was further analyzed via a double-mutant cycle analysis utilizing N’-methylnicotinium, which indicated a hydrogen bond in α6β2 with a ΔΔG of 2.6 kcal/mol. Thus, even though nicotine does not make the conserved cation-π interaction with Trp149, it still makes a functional hydrogen bond to its associated backbone carbonyl.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Post, Michael R.0000-0002-3214-7619
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2017 American Chemical Society. Received: March 8, 2017; Published: March 13, 2017. This work was supported by the NIH (NS 34407, DA019375). MRP was supported by an NIH/NRSA training grant: 5 T32 GM07616. We thank Merouane Bencherif and Daniel Yohannes (Targacept) for gifts of TC299423.
Funding AgencyGrant Number
NIHNS 34407
NIH Predoctoral FellowshipT32 GM07616
Issue or Number:13
PubMed Central ID:PMC6075822
Record Number:CaltechAUTHORS:20170314-072647704
Persistent URL:
Official Citation:Probing for and Quantifying Agonist Hydrogen Bonds in α6β2 Nicotinic Acetylcholine Receptors Michael R. Post, Henry A. Lester, and Dennis A. Dougherty Biochemistry 2017 56 (13), 1836-1840 DOI: 10.1021/acs.biochem.7b00213
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:75083
Deposited By: Tony Diaz
Deposited On:14 Mar 2017 15:28
Last Modified:15 Nov 2021 16:30

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