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Research ArticleArticle

Glycine Hinges with Opposing Actions at the Acetylcholine Receptor-Channel Transmitter Binding Site

Prasad Purohit and Anthony Auerbach
Molecular Pharmacology March 2011, 79 (3) 351-359; DOI: https://doi.org/10.1124/mol.110.068767
Prasad Purohit
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Anthony Auerbach
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Abstract

The extent to which agonists activate synaptic receptor-channels depends on both the intrinsic tendency of the unliganded receptor to open and the amount of agonist binding energy realized in the channel-opening process. We examined mutations of the nicotinic acetylcholine receptor transmitter binding site (α subunit loop B) with regard to both of these parameters. αGly147 is an “activation” hinge where backbone flexibility maintains high values for intrinsic gating, the affinity of the resting conformation for agonists and net ligand binding energy. αGly153 is a “deactivation” hinge that maintains low values for these parameters. αTrp149 (between these two glycines) serves mainly to provide ligand binding energy for gating. We propose that a concerted motion of the two glycine hinges (plus other structural elements at the binding site) positions αTrp149 so that it provides physiologically optimal binding and gating function at the nerve-muscle synapse.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS064969].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.068767.

  • ABBREVIATIONS:

    AChR
    nicotinic acetylcholine receptor
    ACh
    acetylcholine
    R
    resting-closed AChRs
    R*
    active-open state AChRs
    PBS
    phosphate-buffered saline
    wt
    wild type
    Po
    open probability
    R/E
    rate-equilibrium
    Cho
    choline.

  • Received September 7, 2010.
  • Accepted November 29, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (3)
Molecular Pharmacology
Vol. 79, Issue 3
1 Mar 2011
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Research ArticleArticle

Glycine Hinges with Opposing Actions at the Acetylcholine Receptor-Channel Transmitter Binding Site

Prasad Purohit and Anthony Auerbach
Molecular Pharmacology March 1, 2011, 79 (3) 351-359; DOI: https://doi.org/10.1124/mol.110.068767

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Research ArticleArticle

Glycine Hinges with Opposing Actions at the Acetylcholine Receptor-Channel Transmitter Binding Site

Prasad Purohit and Anthony Auerbach
Molecular Pharmacology March 1, 2011, 79 (3) 351-359; DOI: https://doi.org/10.1124/mol.110.068767
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