Class A GPCRs: a multifaceted reality

[摘要] The research group led by Ray Stevens has recently crystallized human A_2A adenosine receptor (A_2AAR) bound to a pharmacological agonist, the compound UK-432097. This new high-resolution structure (RCSB ID: 3QAK) joins the already existing A_2AAR bound to the antagonist ZM2451385 (RCSB ID: 3EML), and enriches the variety of X-ray resolved, class A, G protein-coupled receptors (GPCRs): bovine and squid (rhod)opsins (Rh), turkey β₁- and human β₂-adrenergic receptors (β₁AR and β₂AR), human CXCR4 chemokine receptor and human D3 dopamine receptor (D3R). To shed light on the molecular mechanism of A_2AAR activation, the authors analyse in detail the agonist- and antagonist-bound structures, comparing binding modes and highlighting local changes, in an attempt to recognize the conformational modifications of the receptor at the very beginning of the signal transduction pathway. Authors describe at atomic level the ligand–receptor interaction network, identifying and evaluating all the residues involved in the molecular recognition process. They connect affinity and selectivity of the UK-432097 agonist to the very high number of interactions between ligand and receptor. Among these, they single out the ribose ring as determinant for discriminating between agonistic or antagonistic effects. They report how the binding of the UK-432097 activator induces a coordinated motion of helix VI, which rotates by approximately 30° clockwise with respect to helix V; at the same time, helix VII exhibits a seesaw-like movement around the ribose ring. The authors point out that, while helices I to IV compose a rigid core, helices V, VI and VII are involved in macroscopic rearrangements with spring-like motions. The authors conclude the paper suggesting that, while other activators on different GPCRs shift the dynamic equilibrium between multiple receptor conformations, the agonist UK-432097 stabilizes only one receptor conformation.