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Publication Abstract from PubMed

The G protein-coupled adenosine A2A receptor (A2AAR) is an important new (potential) drug target in immuno-oncology, and for neurodegenerative diseases. Preladenant and its derivatives belong to the most potent A2AAR antagonists displaying exceptional selectivity. While crystal structures of the human A2AAR have been solved, mostly using the A2A-StaR2 protein that bears 9 point mutations, co-crystallization with Preladenant derivatives has so far been elusive. We developed a new A2AAR construct harboring a single point mutation (S913.39K) which renders it extremely thermostable. This allowed the co-crystallization of two novel Preladenant derivatives, the polyethylene glycol-conjugated (PEGylated) PSB-2113, and the fluorophore-labeled PSB-2115. The obtained crystal structures (2.25 A and 2.6 A resolution) provide explanations for the high potency and selectivity of Preladenant derivatives. They represent the first crystal structures of a GPCR in complex with PEG- and fluorophore-conjugated ligands. The applied strategy is predicted to be applicable to further class A GPCRs.

Single Stabilizing Point Mutation Enables High-Resolution Co-Crystal Structures of the Adenosine A2A Receptor with Preladenant Conjugates.,Claff T, Klapschinski TA, Subhramanyam UKT, Vaassen VJ, Schlegel JG, Vielmuth C, Voss JH, Labahn J, Muller CE Angew Chem Int Ed Engl. 2022 Feb 17. doi: 10.1002/anie.202115545. PMID:35174942^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.