The 2.6 Angstrom Crystal Structure of a Human A _2A Adenosine Receptor Bound to an Antagonist

TLDR

Adenosine GPCRs mediate extracellular adenosine signaling and are inhibited by caffeine. We solved the 2.6‑Å crystal structure of the human A2A adenosine receptor bound to the selective antagonist ZM241385. The structure shows four extracellular disulfide bridges, a distinct ligand‑binding pocket formed by subtle transmembrane helix rearrangements, and that ZM241385 binds in an extended, perpendicular orientation that restricts a key tryptophan residue, underscoring the importance of extracellular loops and the helical core in ligand recognition.

Abstract

The adenosine class of heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) mediates the important role of extracellular adenosine in many physiological processes and is antagonized by caffeine. We have determined the crystal structure of the human A 2A adenosine receptor, in complex with a high-affinity subtype-selective antagonist, ZM241385, to 2.6 angstrom resolution. Four disulfide bridges in the extracellular domain, combined with a subtle repacking of the transmembrane helices relative to the adrenergic and rhodopsin receptor structures, define a pocket distinct from that of other structurally determined GPCRs. The arrangement allows for the binding of the antagonist in an extended conformation, perpendicular to the membrane plane. The binding site highlights an integral role for the extracellular loops, together with the helical core, in ligand recognition by this class of GPCRs and suggests a role for ZM241385 in restricting the movement of a tryptophan residue important in the activation mechanism of the class A receptors.