Abstract
Adenosine receptors (ARs) comprise the P1 class of purinergic receptors and belong to the largest family of integral membrane proteins in the human genome, the G protein-coupled receptors (GPCRs). ARs are classified into four subtypes, A1, A2A, A2B, and A3, which are all activated by extracellular adenosine, and play central roles in a broad range of physiological processes, including sleep regulation, angiogenesis and modulation of the immune system. ARs are potential therapeutic targets in a variety of pathophysiological conditions, including sleep disorders, cancer, and dementia, which has made them important targets for structural biology. Over a decade of research and innovation has culminated with the publication of more than 30 crystal structures of the human adenosine A2A receptor (A2AR), making it one of the best structurally characterized GPCRs at the atomic level. In this review we analyze the structural data reported for A2AR that described for the first time the binding of mode of antagonists, including newly developed drug candidates, synthetic and endogenous agonists, sodium ions and an engineered G protein. These structures have revealed the key conformational changes induced upon agonist and G protein binding that are central to signal transduction by A2AR, and have highlighted both similarities and differences in the activation mechanism of this receptor compared to other class A GPCRs. Finally, comparison of A2AR with the recently solved structures of A1R has provided the first structural insight into the molecular determinants of ligand binding specificity in different AR subtypes.
Highlights
Key Concepts1. A2AR crystallization: selection of different conformational states Structure determination of A2AR required the application of novel protein engineering techniques to lock the receptor in defined conformational states and facilitate the growth of crystals that diffract to high resolution
Purinergic signaling is predominantly mediated by extracellular purine nucleosides and nucleotides, including adenosine and adenosine triphosphate (ATP), and by purine bases such as caffeine and xanthine
A decade of research and innovation has culminated in the crystallization of more than 30 structures of human A2AR in complex with one inverse agonist, 11 antagonists and four agonists, as well as an engineered G protein
Summary
1. A2AR crystallization: selection of different conformational states Structure determination of A2AR required the application of novel protein engineering techniques to lock the receptor in defined conformational states and facilitate the growth of crystals that diffract to high resolution. 2. Structural determinants of A2AR ligand binding and selectivity The atomic resolution structural features of A2AR that dictate which ligands it can bind and whether the ligands act as agonists, to promote signaling, or antagonists, to block signaling. 3. Ligand-induced activation of A2AR The molecular changes that are induced in A2AR by agonist binding, which facilitate G protein coupling and signal transduction. 4. Structural diversity of the adenosine receptor family The difference in the primary and ternary structure between the four AR subtypes that is responsible for their ligand-binding specificity and pharmacological profiles
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