title: A neoceptor approach to unraveling microscopic interactions between the human A2A adenosine receptor and its agonists.
abstract: Strategically mutated neoceptors, e.g., with anionic residues in TMs 3 and 7 intended for pairing with positively charged amine-modified nucleosides, were derived from the antiinflammatory A(2A) adenosine receptor (AR). Adenosine derivatives functionalized at the 5', 2, and N(6) positions were synthesized. The T88D mutation selectively enhanced the binding of the chain-length-optimized 5'-(2-aminoethyl)uronamide but not 5'-(2-hydroxyethyl)uronamide, suggesting a critical role of the positively charged amine. Combination of this modification with the N(6)-(2-methylbenzyl) group enhanced affinity at the Q89D- and N181D- but not the T88D-A(2A)AR. Amino groups placed near the 2- or N(6)-position only slightly affected the binding to mutant receptors. The 5'-hydrazide MRS3412 was 670- and 161-fold enhanced, in binding and functionally, respectively, at the Q89D-A(2A)AR compared to the wild-type. Thus, we identified and modeled pairs of A(2A)AR-derived neoceptor-neoligand, which are pharmacologically orthogonal with respect to the native species.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. kajacobs@helix.nih.gov
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Michihiro
authors.initials: M
authors.lastname: Ohno
authors.forename: Heng T
authors.initials: HT
authors.lastname: Duong
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Kim
authors.forename: Susanna
authors.initials: S
authors.lastname: Tchilibon
authors.forename: Michal
authors.initials: M
authors.lastname: Cesnek
authors.forename: Antonín
authors.initials: A
authors.lastname: Holý
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
mesh_terms: D000241:Adenosine / Q000819:agonists* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D011994:Recombinant Proteins / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D008024:Ligands; D043705:Receptor, Adenosine A2A; D011994:Recombinant Proteins; D000241:Adenosine
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