Structure-Based Design of Reactive Nucleosides for Site-Specific Modification of the A2A Adenosine Receptor.

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

SUBMITTER: Moss SM 

PROVIDER: S-EPMC4160753 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature