Structure of an agonist-bound human A2A adenosine receptor

By Fei Xu, Huixian Wu, Vsevolod Katritch, G. Han, Kenneth A. Jacobson, Zhang-Guo Gao, Vadim Cherezov, Raymond C. Stevens. Science, 2011

819 citations recorded by the source corpus.

Changes associated with conformationally selective agonist binding shed light on G protein–coupled receptor activation. Activation of G protein–coupled receptors upon agonist binding is a critical step in the signaling cascade for this family of cell surface proteins. We report the crystal structure of the A2A adenosine receptor (A2AAR) bound to an agonist UK-432097 at 2.7 angstrom resolution. Relative to inactive, antagonist-bound A2AAR, the agonist-bound structure displays an outward tilt and rotation of the cytoplasmic half of helix VI, a movement of helix V, and an axial shift of helix III, resembling the changes associated with the active-state opsin structure. Additionally, a seesaw movement of helix VII and a shift of extracellular loop 3 are likely specific to A2AAR and its ligand. The results define the molecule UK-432097 as a “conformationally selective agonist” capable of receptor stabilization in a specific active-state configuration.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/7b632fa6e889f418cf73ce35bb6800604fa80b20

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Citations in the corpus

Loss of constitutive activity is correlated with increased thermostability of the human adenosine A2A receptor (2013, background): “Significant progress has been made through the development of GPCR fusion proteins, where a T4 lysozyme replaces the conformationally dynamic third intracellular loop (ICL3), for example (Cherezov et al., 2007; Jaakola et al., 2008; Chien et al., 2010; Wu et al., 2010; 2012; Shimamura et al., 2011; ”
Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions (2012, background): “One of the waters in this cluster stabilizes the conformation of a nonproline kink in helix III by forming hydrogen bonds with both the mainchain carboxyl of Ile803.28 and the main-chain nitrogen of Val843.”
The Protein Structure Initiative: achievements and visions for the future (2012, background): “Some important integral membrane protein structures, including several G protein-coupled receptors, known as GPCRs, and their complexes with ligands, have recently been determined in PSI-funded projects using both X-ray crystallography [62-71] andNMR spectroscopy [72,73].”
Lifting the lid on GPCRs: the role of extracellular loops (2011, methodology): “There are crystal structures for the A2AR-T4L bound to the antagonist ZM241385 (Jaakola et al., 2008) and the agonist UK-432097 (Xu et al., 2011).”
Multiple conformational states in retrospective virtual screening – homology models vs. crystal structures: beta-2 adrenergic receptor case study (2015, neutral): “A2AR 3QAK [25] 2.”
Cryo-EM structure of the adenosine A2A receptor coupled to an engineered heterotrimeric G protein (2018, neutral): “Construction of the 399 thioredoxin-A2AR fusion protein and C-terminally truncated A2AR (1-317), both containing 400 the N154A mutation, is described elsewhere(29).”