Distinct Properties of Glycine Receptor β+/α− Interface

Shan, Qiang; Han, Lu; Lynch, Joseph W.

doi:10.1074/jbc.m111.337741

Cited by 6 publications

(2 citation statements)

References 39 publications

(60 reference statements)

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“…This perhaps reiterates that the structure of the agonist-binding site and the binding mode of various agonists are determined not only by ECD amino acid identity but also by length of loops and the orientation of side chains outside of the agonist-binding site (Liu et al, 2005 ; Kehoe et al, 2009 ; Xiu et al, 2009 ). Indeed, Loop A has been proposed as the main determinant of the different agonist recognition by α and β GlyR isoforms (Shan et al, 2012 ), yet their loop A sequences are 100% identical.…”

Section: Chemical and Structural Insights Into Agonist Recognition: Imentioning

confidence: 99%

Principles of agonist recognition in Cys-loop receptors

Lynagh

Pless

2014

Front. Physiol.

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Cys-loop receptors are ligand-gated ion channels that are activated by a structurally diverse array of neurotransmitters, including acetylcholine, serotonin, glycine, and GABA. After the term “chemoreceptor” emerged over 100 years ago, there was some wait until affinity labeling, molecular cloning, functional studies, and X-ray crystallography experiments identified the extracellular interface of adjacent subunits as the principal site of agonist binding. The question of how subtle differences at and around agonist-binding sites of different Cys-loop receptors can accommodate transmitters as chemically diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework to understand the atomic determinants involved in how these valuable therapeutic targets recognize and bind their ligands.

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Section: Chemical and Structural Insights Into Agonist Recognition: Imentioning

confidence: 99%

Principles of agonist recognition in Cys-loop receptors

Lynagh

Pless

2014

Front. Physiol.

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“…To this we add the very significant complication that the overwhelming majority of human pLGICs of physiological and pharmacological relevance are heteromeric, with distinct subunit combinations that display unique biophysical and pharmacological profiles. These assemblies are unevenly distributed throughout the CNS and its periphery, and the heterogeneity provides an opportunity for the development of ligands with receptorsubtype specificity (Dutertre et al, 2012;Shan et al, 2012;Webb & Lynch, 2007). In large part, owing to difficulties in the recombinant protein production of heteromeric samples, structural studies are largely restricted to homomeric pLGICs, with a limited capacity to characterize the details of selectivity that can guide the development of selective chemical probes necessary to support fundamental studies or drug discovery.…”

Section: Introductionmentioning

confidence: 99%

Engineering a surrogate human heteromeric α/β glycine receptor orthosteric site exploiting the structural homology and stability of acetylcholine-binding protein

Dawson

Trumper

Souza

et al. 2019

Int Union Crystallogr J

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Pair of Residue Substitutions at the Outer Mouth of the Channel Pore Act as Inputs for a Boolean Logic “OR” Gate Based on the Glycine Receptor

Han

Shan

2020

ACS Chem. Neurosci.

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The glycine receptor (GlyR) is a ligand-activated chloride channel, whose mutations are the major cause of hereditary hyperekplexia. The hyperekplexia-causing R271Q mutation, which is located at the extracellular outer mouth of the channel pore, dramatically impairs the GlyR function manifesting a reduced sensitivity toward glycine. This study reports that a second mutation, S273D, rescues the function of the R271Q GlyR to that of the wild-type (WT) GlyR. Surprisingly, the S273D mutation, when introduced to the WT GlyR, does not further increase the receptor function. In other words, the compromised function of the 271Q 273S GlyR (i.e., the R271Q GlyR) can be rescued to WT levels by the introduction of either, or both, of the Q271R and S273D substitutions. From the perspective of Boolean logic gates, the Q271R and S273D substitutions act as inputs for an OR gate based on the GlyR. Further experiments revealed that the negative-charge carried by the 273 residue is essential for the expression of the OR gate and that the expression of the OR gate is residue-position-specific. In addition, mechanistic investigation implied that the 273 residue influences the 271 residue, which might underpin the unique nonadditive OR gate relationship between these two residues. Such an ion-channel-based OR gate, expressing output in the form of electrical current, could potentially be developed to digitally manipulate neuronal activity.

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Distinct Properties of Glycine Receptor β+/α− Interface

Cited by 6 publications

References 39 publications

Principles of agonist recognition in Cys-loop receptors

Principles of agonist recognition in Cys-loop receptors

Engineering a surrogate human heteromeric α/β glycine receptor orthosteric site exploiting the structural homology and stability of acetylcholine-binding protein

Pair of Residue Substitutions at the Outer Mouth of the Channel Pore Act as Inputs for a Boolean Logic “OR” Gate Based on the Glycine Receptor

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