The study presents two crystal structures of the thermostabilized human adenosine A2A receptor (A2AR-GL31) bound to its endogenous agonist adenosine and the synthetic agonist NECA. These structures represent an intermediate conformation between the inactive and fully activated states, with the cytoplasmic end of transmembrane helix 6 partially occluding the G protein binding site. The adenine substituent of the agonists binds similarly to the chemically-related region of the inverse agonist ZM241385, but the agonists contain a ribose group that extends into the ligand binding pocket, interacting with conserved residues in H7. In contrast, the inverse agonist ZM241385 does not interact with these residues, suggesting that it sterically prevents the conformational change in H5, which is crucial for receptor activation. Comparison of the agonist-bound structures of A2AR with those of β-adrenoceptors (βARs) reveals that the contraction of the ligand binding pocket caused by the inward motion of helices 3, 5, and 7 may be a common feature in the activation of all GPCRs. The study also discusses the structural similarities and differences between agonist binding to A2AR and βARs, highlighting the importance of specific residues in H7 for receptor activation.The study presents two crystal structures of the thermostabilized human adenosine A2A receptor (A2AR-GL31) bound to its endogenous agonist adenosine and the synthetic agonist NECA. These structures represent an intermediate conformation between the inactive and fully activated states, with the cytoplasmic end of transmembrane helix 6 partially occluding the G protein binding site. The adenine substituent of the agonists binds similarly to the chemically-related region of the inverse agonist ZM241385, but the agonists contain a ribose group that extends into the ligand binding pocket, interacting with conserved residues in H7. In contrast, the inverse agonist ZM241385 does not interact with these residues, suggesting that it sterically prevents the conformational change in H5, which is crucial for receptor activation. Comparison of the agonist-bound structures of A2AR with those of β-adrenoceptors (βARs) reveals that the contraction of the ligand binding pocket caused by the inward motion of helices 3, 5, and 7 may be a common feature in the activation of all GPCRs. The study also discusses the structural similarities and differences between agonist binding to A2AR and βARs, highlighting the importance of specific residues in H7 for receptor activation.