The crystallographic structure of the human adenosine A2A receptor in a high-affinity antagonist-bound state: implications for GPCR drug screening and design.

G-protein-coupled receptors, GPCRs, are key elements in the vertebrate signal transduction system, and constitute the majority of drug targets. Solved 10 years ago, the crystal structure of inactive state rhodopsin with covalently linked cis-retinal as an inverse agonist provided the first near-atomic view of the GPCR architecture. The inherent instability and low abundance from both natural and recombinant sources are only two factors that long hampered a similar structure elucidation of other GPCRs that have diffusible ligands such as neurotransmitters and hormones. However, in the last three years this situation has changed with the advent of structures of the human adenosine A2A receptor, avian beta1-adrenoceptor, human beta2-adrenoceptor, squid rhodopsin and activated form of bovine (rhod)opsin. In this review the structural features of the human adenosine A2A receptor and the main differences with beta-adrenoceptor and rhodopsin structures are highlighted. Furthermore, the implications of this structural information for drug screening and structure-based drug design will be discussed. Copyright (c) 2010 Elsevier Ltd. All rights reserved.