The study presents two crystal structures of the thermostabilized human adenosine A₂A receptor (A₂A R-GL31) bound to its endogenous agonist adenosine and the synthetic agonist NECA. These structures represent an intermediate conformation between the inactive and active states of G protein-coupled receptors (GPCRs), as they share features of fully activated GPCRs but have a partially occluded G protein binding site in transmembrane helix 6. Both agonists bind to a similar region of the receptor, with the adenine ring interacting with conserved residues in transmembrane helix 7 (Ser277 and His278) and non-polar interactions with residues in helix 3. In contrast, the inverse agonist ZM241385 does not interact with these residues and prevents conformational changes in helix 5, acting as an inverse agonist. Comparison with β-adrenoceptor structures suggests that the inward motion of helices 3, 5, and 7 may be a common feature in GPCR activation. The structures of A₂A R-GL31 and β-adrenoceptors show similar conformational changes, with the cytoplasmic ends of helices 5 and 6 moving away from the receptor core, opening a cleft for G protein binding. The thermostabilized A₂A R-GL31 construct, with four point mutations, improves thermostability but may decouple high-affinity agonist binding from the formation of the active state R*. The structures suggest that A₂A R-GL31 is in an intermediate conformation between R and R*, consistent with structural analysis. The two structures of A₂A R-GL31 bound to adenosine and NECA have resolutions of 3.0 Å and 2.6 Å, respectively. Global alignments with ZM241385-bound A₂A-T4L show structural homology, with an rmsd of 0.66 Å for selected atoms. The most significant differences are in helix 3, where a 2 Å shift and a bulge in helix 5 are observed. These differences are similar to those in β-adrenoceptor structures, indicating conformational changes responsible for the R* state. The structures of A₂A R-GL31 and β-adrenoceptor-Nb80 complexes suggest that the bulge in helix 5 is a common feature of agonist activation, while inverse agonists prevent its formation. The binding of agonists to A₂A R involves interactions with helices 3 and 7, absent in the inverse agonist ZM241385. The formation of the bulge in helix 5 is crucial for receptor activation, as it causes inward movement of residues and sterically blocks ZThe study presents two crystal structures of the thermostabilized human adenosine A₂A receptor (A₂A R-GL31) bound to its endogenous agonist adenosine and the synthetic agonist NECA. These structures represent an intermediate conformation between the inactive and active states of G protein-coupled receptors (GPCRs), as they share features of fully activated GPCRs but have a partially occluded G protein binding site in transmembrane helix 6. Both agonists bind to a similar region of the receptor, with the adenine ring interacting with conserved residues in transmembrane helix 7 (Ser277 and His278) and non-polar interactions with residues in helix 3. In contrast, the inverse agonist ZM241385 does not interact with these residues and prevents conformational changes in helix 5, acting as an inverse agonist. Comparison with β-adrenoceptor structures suggests that the inward motion of helices 3, 5, and 7 may be a common feature in GPCR activation. The structures of A₂A R-GL31 and β-adrenoceptors show similar conformational changes, with the cytoplasmic ends of helices 5 and 6 moving away from the receptor core, opening a cleft for G protein binding. The thermostabilized A₂A R-GL31 construct, with four point mutations, improves thermostability but may decouple high-affinity agonist binding from the formation of the active state R*. The structures suggest that A₂A R-GL31 is in an intermediate conformation between R and R*, consistent with structural analysis. The two structures of A₂A R-GL31 bound to adenosine and NECA have resolutions of 3.0 Å and 2.6 Å, respectively. Global alignments with ZM241385-bound A₂A-T4L show structural homology, with an rmsd of 0.66 Å for selected atoms. The most significant differences are in helix 3, where a 2 Å shift and a bulge in helix 5 are observed. These differences are similar to those in β-adrenoceptor structures, indicating conformational changes responsible for the R* state. The structures of A₂A R-GL31 and β-adrenoceptor-Nb80 complexes suggest that the bulge in helix 5 is a common feature of agonist activation, while inverse agonists prevent its formation. The binding of agonists to A₂A R involves interactions with helices 3 and 7, absent in the inverse agonist ZM241385. The formation of the bulge in helix 5 is crucial for receptor activation, as it causes inward movement of residues and sterically blocks Z