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Molecular Pharmacology

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Research ArticleArticle

A Novel Nonribose Agonist, LUF5834, Engages Residues That Are Distinct from Those of Adenosine-Like Ligands to Activate the Adenosine A2a Receptor

J. Robert Lane, Carmen Klein Herenbrink, Gerard J. P. van Westen, Jelle A. Spoorendonk, Carsten Hoffmann and Adriaan P. IJzerman
Molecular Pharmacology March 2012, 81 (3) 475-487; DOI: https://doi.org/10.1124/mol.111.075937
J. Robert Lane
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Carmen Klein Herenbrink
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Gerard J. P. van Westen
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Jelle A. Spoorendonk
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Carsten Hoffmann
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Adriaan P. IJzerman
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Abstract

The recent publication of both the antagonist- and agonist-bound structures of the adenosine A2A receptor have revealed much about how a ligand may bind to a receptor and cause the conformational changes associated with agonist-mediated activation. In particular, the agonist-bound structure revealed key interactions between the ribose group of adenosine-derived agonists and amino acids in the receptor binding pocket that lead to receptor activation. However, agonists without a ribose group also exist, and we wondered whether such compounds occupy the same agonist binding site. Therefore we used a mutagenesis approach in this study to investigate the mode of binding of 2-amino-4-(4-hydroxyphenyl)- 6-(1H-imidazol-2-ylmethylsulfanyl)pyridine-3,5-dicarbonitrile (LUF5834), a potent partial agonist without a ribose moiety, compared with the adenosine-derived reference agonist 2-[p-(2-carboxyethyl)phenyl-ethylamino]-5′-N-ethylcarboxamidoadenosine (CGS21680). Mutation of the orthosteric residue Phe168 to alanine abrogated the function of both agonists. However, mutation to alanine of residues Thr88 and Ser277 shown by the crystal structures to interact with the ribose group of adenosine-like ligands had no effect on the potency of LUF5834. Furthermore, alanine mutation of Asn253, which makes a hydrogen-bonding interaction with the exocyclic nitrogen of the adenine ring, had minimal effect on LUF5834 affinity but removed agonist activity of this ligand. Mutation of other residues, such as the highly conserved Trp246 or Glu13, had significant deleterious effects on the function of CGS21680 but little effect on LUF5834. In summary, our findings suggest that this class of agonist interacts with distinct residues to activate the receptor compared with classic adenosine derived agonists.

Footnotes

  • This work was supported by the Netherlands Organization for Scientific Research [NWO VENI Grant 863.09.018] (to J.R.L.); a Monash University Larkins Fellowship (to J.R.L.); and Tibotec BVBA (to G.J.P.v.W.).

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

    http://dx.doi.org/10.1124/mol.111.075937.

  • ABBREVIATIONS:

    AR
    adenosine receptor
    GPCR
    G protein-coupled receptor
    ZM241385
    4-{2-[7-amino-2-(2-furyl)-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-yl-amino]ethyl} phenol
    ECL
    extracellular loop
    LUF5834
    2-amino-4-(4-hydroxyphenyl)-6-(1H-imidazol-2-ylmethylsulfanyl)-pyridine-3,5-dicarbonitrile
    CGS21680
    2-[p-(2-carboxyethyl)phenylethylamino]-5′-N-ethyl-carboxamidoadenosine
    CFP
    cyan fluorescent protein
    FlAsH
    fluorescein arsenical hairpin binder
    PSB-603
    8-[4-[4-(4-chlorophenzyl)piperazide-1-sulfonyl)phenyl]]-1-propylxanthine
    ADA
    adenosine deaminase
    GPCR
    G protein-coupled receptor
    BSA
    bovine serum albumin
    HEK
    human embryonic kidney
    GFP
    green fluorescent protein
    TBS
    Tris-buffered saline
    PDB
    Protein Data Bank
    MOE
    Molecular Operating Environment
    ELISA
    enzyme-linked immunosorbent assay
    UK 432097
    6-(2,2-diphenylethylamino)-9-((2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxytetrahydrofuran-2-yl)-N-(2-(3-(1-(pyridin-2-yl)piperidin-4-yl)ureido)ethyl)-9H-purine-2-carboxamide
    NECA
    5′-N-ethylcarboxamidoadenosine
    TM
    transmembrane.

  • Received September 18, 2011.
  • Accepted December 21, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (3)
Molecular Pharmacology
Vol. 81, Issue 3
1 Mar 2012
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Research ArticleArticle

Nonribose Agonist for Adenosine Receptors

J. Robert Lane, Carmen Klein Herenbrink, Gerard J. P. van Westen, Jelle A. Spoorendonk, Carsten Hoffmann and Adriaan P. IJzerman
Molecular Pharmacology March 1, 2012, 81 (3) 475-487; DOI: https://doi.org/10.1124/mol.111.075937

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Research ArticleArticle

Nonribose Agonist for Adenosine Receptors

J. Robert Lane, Carmen Klein Herenbrink, Gerard J. P. van Westen, Jelle A. Spoorendonk, Carsten Hoffmann and Adriaan P. IJzerman
Molecular Pharmacology March 1, 2012, 81 (3) 475-487; DOI: https://doi.org/10.1124/mol.111.075937
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