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Molecular Pharmacology

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Research ArticleArticle

Exploring the Binding Site Crevice of a Family B G Protein-Coupled Receptor, the Type 1 Corticotropin Releasing Factor Receptor

Kostas Gkountelias, Maria Papadokostaki, Jonathan A. Javitch and George Liapakis
Molecular Pharmacology October 2010, 78 (4) 785-793; DOI: https://doi.org/10.1124/mol.110.065474
Kostas Gkountelias
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Maria Papadokostaki
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Jonathan A. Javitch
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George Liapakis
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Abstract

Family B of G protein-coupled receptors (GPCRs) is composed of receptors that bind peptides, such as secretin, glucagon, parathyroid hormone, and corticotropin releasing factor (CRF), which play critical physiological roles. These receptors, like all GPCRs, share a common structural motif of seven membrane-spanning segments, which have been proposed to bind small ligands, such as antalarmin, a nonpeptide antagonist of the type 1 receptor for CRF (CRF1). This leads to the hypothesis that as for family A GPCRs, the binding sites of small ligands for family B GPCRs are on the surface of a water-accessible crevice, the binding-site crevice, which is formed by the membrane-spanning segments and extends from the extracellular surface of the receptor into the plane of the membrane. To test this hypothesis we have begun to obtain structural information about family B GPCRs, using as a prototype the CRF1, by determining the ability of sulfhydryl-specific methanethiosulfonate derivatives, such as the methanethiosulfonate-ethylammonium (MTSEA), to react with CRF1 and thus irreversibly inhibit 125I-Tyr0-sauvagine binding. We found that MTSEA inhibited 125I-Tyr0-sauvagine binding to CRF1 and that antalarmin protected against this irreversible inhibition. To identify the susceptible cysteine(s), we mutated, one at a time, four endogenous cysteines to serine. Mutation to serine of Cys211, Cys233, or Cys364 decreased the susceptibility of sauvagine binding to irreversible inhibition by MTSEA. Thus, Cys211, Cys233, and Cys364 at the cytoplasmic ends of the third, fourth, and seventh membrane-spanning segments, respectively, are exposed in the binding site crevice of CRF1.

Footnotes

  • This research project was supported by a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award (to G.L.).

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

    doi:10.1124/mol.110.065474.

  • ABBREVIATIONS:

    GPCR
    G protein-coupled receptor
    CRF
    corticotropin-releasing factor
    CRF1
    type 1 receptor for the corticotropin releasing factor
    TM
    transmembrane
    MTS
    methanethiosulfonate
    MTSEA
    methanethiosulfonate-ethylammonium
    MTSET
    methanethiosulfonate-trimethylammonium
    MTSES
    methanethiosulfonate-ethylsulfonate
    WT
    wild type
    HEK
    human embryonic kidney
    PBS
    phosphate-buffered saline
    ANOVA
    analysis of variance.

  • Received April 8, 2010.
  • Accepted July 27, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (4)
Molecular Pharmacology
Vol. 78, Issue 4
1 Oct 2010
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Research ArticleArticle

Exploring the Binding Site Crevice of a Family B G Protein-Coupled Receptor, the Type 1 Corticotropin Releasing Factor Receptor

Kostas Gkountelias, Maria Papadokostaki, Jonathan A. Javitch and George Liapakis
Molecular Pharmacology October 1, 2010, 78 (4) 785-793; DOI: https://doi.org/10.1124/mol.110.065474

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Research ArticleArticle

Exploring the Binding Site Crevice of a Family B G Protein-Coupled Receptor, the Type 1 Corticotropin Releasing Factor Receptor

Kostas Gkountelias, Maria Papadokostaki, Jonathan A. Javitch and George Liapakis
Molecular Pharmacology October 1, 2010, 78 (4) 785-793; DOI: https://doi.org/10.1124/mol.110.065474
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