{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Moss SM"],"funding":["Intramural NIH HHS","National Institute of Diabetes and Digestive and Kidney Diseases"],"pagination":["1043-8"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4160753"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["5(9)"],"pubmed_abstract":["Adenosine receptors (ARs) are members of the G protein-coupled receptor (GPCR) superfamily and have shown much promise as therapeutic targets. We have used an agonist-bound A2AAR X-ray crystallographic structure to design a chemically reactive agonist for site-specific chemical modification of the receptor. To further explore and chemically engineer its binding cavity, a 2-nitrophenyl active ester was attached through an elongated chain at adenine C2 position. This general structure was designed for irreversible transfer of a terminal acyl group to a nucleophilic amino group on the A2AAR. Preincubation with several O-acyl derivatives prevented radioligand binding that was not regenerated upon extensive washing. In silico receptor docking suggested two lysine residues (second extracellular loop) as potential target sites for an O-acetyl derivative (MRS5854, 3a), and site-directed mutagenesis indicated that K153 but not K150 is essential. Similarly, a butyl azide for click reaction was incorporated in the active ester moiety (3b). These promising results indicate a stable, covalent modification of the receptor by several reactive adenosine derivatives, which could be chemical tools for future imaging, structural probing, and drug discovery. Thus, structure-based ligand design has guided the site-specific modification of a GPCR."],"journal":["ACS medicinal chemistry letters"],"pubmed_title":["Structure-Based Design of Reactive Nucleosides for Site-Specific Modification of the A2A Adenosine Receptor."],"pmcid":["PMC4160753"],"funding_grant_id":["ZIA DK031126-07","ZIA DK031117-26","Z01DK-31117-26"],"pubmed_authors":["Jacobson KA","Jayasekara PS","Gao ZG","Paoletta S","Moss SM"],"additional_accession":[]},"is_claimable":false,"name":"Structure-Based Design of Reactive Nucleosides for Site-Specific Modification of the A2A Adenosine Receptor.","description":"Adenosine receptors (ARs) are members of the G protein-coupled receptor (GPCR) superfamily and have shown much promise as therapeutic targets. We have used an agonist-bound A2AAR X-ray crystallographic structure to design a chemically reactive agonist for site-specific chemical modification of the receptor. To further explore and chemically engineer its binding cavity, a 2-nitrophenyl active ester was attached through an elongated chain at adenine C2 position. This general structure was designed for irreversible transfer of a terminal acyl group to a nucleophilic amino group on the A2AAR. Preincubation with several O-acyl derivatives prevented radioligand binding that was not regenerated upon extensive washing. In silico receptor docking suggested two lysine residues (second extracellular loop) as potential target sites for an O-acetyl derivative (MRS5854, 3a), and site-directed mutagenesis indicated that K153 but not K150 is essential. Similarly, a butyl azide for click reaction was incorporated in the active ester moiety (3b). These promising results indicate a stable, covalent modification of the receptor by several reactive adenosine derivatives, which could be chemical tools for future imaging, structural probing, and drug discovery. Thus, structure-based ligand design has guided the site-specific modification of a GPCR.","dates":{"release":"2014-01-01T00:00:00Z","publication":"2014 Sep","modification":"2024-11-14T07:17:13.666Z","creation":"2019-03-27T01:35:33Z"},"accession":"S-EPMC4160753","cross_references":{"pubmed":["25221664"],"doi":["10.1021/ml5002486"]}}