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

Lane, J Robert; Klein Herenbrink, Carmen; van Westen, Gerard J P; Spoorendonk, Jelle A; Hoffmann, Carsten; Ijzerman, Adriaan P


J Robert Lane

Carmen Klein Herenbrink

Gerard J P van Westen

Jelle A Spoorendonk

Carsten Hoffmann

Adriaan P Ijzerman


The recent publication of both the antagonist- and agonist-bound structures of the adenosine A(2A) 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.


Lane, J. R., Klein Herenbrink, C., van Westen, G. J. P., Spoorendonk, J. A., Hoffmann, C., & Ijzerman, A. P. (2012). A Novel Nonribose Agonist, LUF5834, Engages Residues That Are Distinct from Those of Adenosine-Like Ligands to Activate the Adenosine A2a Receptor. Molecular Pharmacology, 81(3), 475-487.

Journal Article Type Article
Acceptance Date Dec 21, 2011
Online Publication Date Feb 16, 2012
Publication Date Mar 1, 2012
Deposit Date Apr 22, 2020
Journal Molecular Pharmacology
Print ISSN 0026-895X
Publisher American Society for Pharmacology and Experimental Therapeutics
Peer Reviewed Peer Reviewed
Volume 81
Issue 3
Pages 475-487
Public URL
Publisher URL

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