Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation

By G. Lebon, Tony Warne, P. Edwards, K. Bennett, Christopher James Langmead, A. Leslie, C. Tate. Nature, 2011

869 citations recorded by the source corpus.

Adenosine receptors and β-adrenoceptors are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins on binding the agonists adenosine or noradrenaline, respectively. GPCRs have similar structures consisting of seven transmembrane helices that contain well-conserved sequence motifs, indicating that they are probably activated by a common mechanism. Recent structures of β-adrenoceptors highlight residues in transmembrane region 5 that initially bind specifically to agonists rather than to antagonists, indicating that these residues have an important role in agonist-induced activation of receptors. Here we present two crystal structures of the thermostabilized human adenosine A2A receptor (A2AR-GL31) bound to its endogenous agonist adenosine and the synthetic agonist NECA. The structures represent an intermediate conformation between the inactive and active states, because they share all the features of GPCRs that are thought to be in a fully activated state, except that the cytoplasmic end of transmembrane helix 6 partially occludes the G-protein-binding site. The adenine substituent of the agonists binds in a similar fashion to the chemically related region of the inverse agonist ZM241385 (ref. 8). Both agonists contain a ribose group, not found in ZM241385, which extends deep into the ligand-binding pocket where it makes polar interactions with conserved residues in H7 (Ser 2777.42 and His 2787.43; superscripts refer to Ballesteros–Weinstein numbering) and non-polar interactions with residues in H3. In contrast, the inverse agonist ZM241385 does not interact with any of these residues and comparison with the agonist-bound structures indicates that ZM241385 sterically prevents the conformational change in H5 and therefore it acts as an inverse agonist. Comparison of the agonist-bound structures of A2AR with the agonist-bound structures of β-adrenoceptors indicates 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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/db25df97172aa1cbb6d5a6a64a66ecc2c330a1b8

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Citations in the corpus

Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions (2012, background): “In the active-like state agonist-bound A2AAR structures (20, 21), the kink in helix III straightens, thereby precluding water binding, which points to a role of water rearrangement at this location in A2AAR activation.”
Lifting the lid on GPCRs: the role of extracellular loops (2011, methodology): “Agonist-induced contraction of the A2AR binding pocket is very similar but involves hydrogen bonding between the agonists and residues at the top of TM7 (Ser and His) rather than TM5 (Lebon et al., 2011).”
Loss of constitutive activity is correlated with increased thermostability of the human adenosine A2A receptor (2013, background): “In contrast to the findings presented here, the thermostabilized GL31, which contains a completely different set of point mutations to the Rag23 construct, exhibited WT levels of constitutive activity in a mammalian cell signalling system.”
The Molecular Basis of G Protein–Coupled Receptor Activation (2018, background): “In these A2aR structures, there are also changes in the cytoplasmic side of the TM region, but they are not as extensive as those observed in the fully activated state: TM5 shifts slightly toward TM6, TM6 moves outward slightly, and TM7 moves inward as much as 4–5 Å (17, 18, 24) (Figure 7).”
Structure-Function of the G-protein-Coupled Receptor Superfamily (2012, background): “49 salt bridge remains intact in the active β2AR -nanobody complex (22), as well as in the active state A2AAR structures (R’’) (19, 20).”