Predicted structure of the extracellular region of ligand-gated ion- channel receptors shows SH2-like and SH3-like domains forming the ligand- binding site

Jill E. Gready, Shoba Ranganathan, Peter R. Schofield, Y. O. Matsuo, Ken Nishikawa

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Fast synaptic neurotransmission is mediated by ligand-gated ion- channel (LGIC) receptors, which include receptors for acetylcholine, serotonin, GABA, glycine, and glutamate. LGICs are pentamers with extracellular ligand-binding domains and form integral membrane ion channels that are selective for cations (acetylcholine and serotonin 5HT3 receptors) or anions (GABA(A) and glycine receptors and the invertebrate glutamate- binding chloride channel). They form a protein superfamily with no sequence similarity to any protein of known structure. Using a 1D-3D structure mapping approach, we have modeled the extracellular ligand-binding domain based on a significant match with the SH2 and SH3 domains of the biotin repressor structure. Refinement of the model based on knowledge of the large family of SH2 and SH3 structures, sequence alignments, and use of structure templates for loop building, allows the prediction of both monomer and pentamer models. These are consistent with medium-resolution electron microscopy structures and with experimental structure/function data from ligand-binding, antibody-binding, mutagenesis, protein-labeling and subunit- linking studies, and glycosylation sites. Also, the predicted polarity of the channel pore calculated from electrostatic potential maps of pentamer models of superfamily members is consistent with known ion selectivities. Using the glycine receptor α1 subunit, which forms homopentamers, the monomeric and pentameric models define the agonist and antagonist (strychnine) binding sites to a deep crevice formed by an extended loop, which includes the invariant disulfide bridge, between the SH2 and SH3 domains. A detailed binding site for strychnine is reported that is in strong agreement with known structure/function data. A site for interaction of the extracellular ligand-binding domain with the activation of the M2 transmembrane helix is also suggested.

LanguageEnglish
Pages983-998
Number of pages16
JournalProtein Science
Volume6
Issue number5
Publication statusPublished - May 1997
Externally publishedYes

Fingerprint

Ligand-Gated Ion Channels
src Homology Domains
Binding Sites
Ligands
Glycine Receptors
Strychnine
Serotonin Receptors
Ion Channels
Glutamic Acid
Glycosylation
Mutagenesis
Chloride Channels
Proteins
Sequence Alignment
Protein Subunits
Cholinergic Receptors
GABA-A Receptors
Invertebrates
Static Electricity
Synaptic Transmission

Keywords

  • 1D-3D structure prediction
  • acetylcholine receptor
  • biotin repressor
  • extracellular ligand-binding domain
  • glycine receptor
  • ligand- gated ion-channel receptors
  • M2 transmembrane helix
  • pentameric channels
  • SH2 and SH3 domains

Cite this

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title = "Predicted structure of the extracellular region of ligand-gated ion- channel receptors shows SH2-like and SH3-like domains forming the ligand- binding site",
abstract = "Fast synaptic neurotransmission is mediated by ligand-gated ion- channel (LGIC) receptors, which include receptors for acetylcholine, serotonin, GABA, glycine, and glutamate. LGICs are pentamers with extracellular ligand-binding domains and form integral membrane ion channels that are selective for cations (acetylcholine and serotonin 5HT3 receptors) or anions (GABA(A) and glycine receptors and the invertebrate glutamate- binding chloride channel). They form a protein superfamily with no sequence similarity to any protein of known structure. Using a 1D-3D structure mapping approach, we have modeled the extracellular ligand-binding domain based on a significant match with the SH2 and SH3 domains of the biotin repressor structure. Refinement of the model based on knowledge of the large family of SH2 and SH3 structures, sequence alignments, and use of structure templates for loop building, allows the prediction of both monomer and pentamer models. These are consistent with medium-resolution electron microscopy structures and with experimental structure/function data from ligand-binding, antibody-binding, mutagenesis, protein-labeling and subunit- linking studies, and glycosylation sites. Also, the predicted polarity of the channel pore calculated from electrostatic potential maps of pentamer models of superfamily members is consistent with known ion selectivities. Using the glycine receptor α1 subunit, which forms homopentamers, the monomeric and pentameric models define the agonist and antagonist (strychnine) binding sites to a deep crevice formed by an extended loop, which includes the invariant disulfide bridge, between the SH2 and SH3 domains. A detailed binding site for strychnine is reported that is in strong agreement with known structure/function data. A site for interaction of the extracellular ligand-binding domain with the activation of the M2 transmembrane helix is also suggested.",
keywords = "1D-3D structure prediction, acetylcholine receptor, biotin repressor, extracellular ligand-binding domain, glycine receptor, ligand- gated ion-channel receptors, M2 transmembrane helix, pentameric channels, SH2 and SH3 domains",
author = "Gready, {Jill E.} and Shoba Ranganathan and Schofield, {Peter R.} and Matsuo, {Y. O.} and Ken Nishikawa",
year = "1997",
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Predicted structure of the extracellular region of ligand-gated ion- channel receptors shows SH2-like and SH3-like domains forming the ligand- binding site. / Gready, Jill E.; Ranganathan, Shoba; Schofield, Peter R.; Matsuo, Y. O.; Nishikawa, Ken.

In: Protein Science, Vol. 6, No. 5, 05.1997, p. 983-998.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Predicted structure of the extracellular region of ligand-gated ion- channel receptors shows SH2-like and SH3-like domains forming the ligand- binding site

AU - Gready, Jill E.

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