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A Novel Non-ribose Agonist, LUF5834, Engages Distinct Residues from that of Adenosine-like Ligands to Activate the Adenosine A2A Receptor.
MedLine Citation:
PMID:  22188926     Owner:  NLM     Status:  Publisher    
The recent publication of both the antagonist bound 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 LUF5834, a potent partial agonist without a ribose moiety, in comparison to the adenosine-derived reference agonist 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 had little effect on LUF5834. In summary our findings suggest that this class of agonist interacts with distinct residues to activate the receptor as compared to classical adenosine derived agonists.
Robert Lane; Carmen Klein Herenbrink; Gerard J P van Western; Jelle A Spoorendonk; Carsten Hoffmann; Ad P Ijzerman
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-12-21
Journal Detail:
Title:  Molecular pharmacology     Volume:  -     ISSN:  1521-0111     ISO Abbreviation:  -     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
1 Monash Institute of Pharmaceutical Sciences, Monash University;
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