Mapping the Allosteric Sites of the A2A Adenosine Receptor

Abstract

The A_2A adenosine receptor (A_2AAR) is a G protein-coupled receptor that is pharmacologically targeted for the treatment of inflammation, sepsis, cancer, neuro-degeneration, and Parkinson's disease. Recently, we applied long-timescale molecular dynamics simulations on two ligand-free receptor conformations, starting from the agonist-bound (PDB ID:3QAK) and antagonist-bound (PDB ID:3EML) X-ray structures. This analysis revealed four distinct conformers of the A_2AAR: the active, intermediate 1, intermediate 2, and inactive. In this study, we apply the fragment-based mapping algorithm, FTMap, on these receptor conformations to uncover five non-orthosteric sites on the A_2AAR. Two sites that are identified in the active conformation are located in the intracellular region of the transmembrane helices (TM) 3/TM4 and the G protein-binding site in the intracellular region between TM2/TM3/TM6/TM7. Three sites are identified in the intermediate 1 and intermediate 2 conformations, annexing a site in the lipid interface of TM5/TM6. Five sites are identified in the inactive conformation, comprising of a site in the intracellular region of TM1/TM7, and in the extracellular region of TM3/TM4 of the A_2AAR. We postulate that these sites on the A_2AAR be screened for allosteric modulators for the treatment of inflammatory and neurological diseases.

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We uncover five non-ortnosteric sites on the A_2A adenosine receptor that can be screened for allosteric modulators for the treatment of inflammatory and neurological diseases. Site one is in the intracellular region of the transmembrane helices (TM) 3/TM4, and site two is the G protein-binding site between TM2/TM3/TM6/TM7. Site three is on the lipid interface of TM5/TM6, site four is in the intracelluar region of TM1/TM7, and site five is in the extracellular region of TM3/TM4.

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