Structure of the Adenosine A₁ Receptor Reveals the Basis for Subtype Selectivity

Highlights

• 3.2 Å resolution antagonist-bound structure of the adenosine A₁ receptor solved

• Major differences found in extracellular loop regions relative to the A_2A structure

• Drug selectivity is predominantly determined by binding site shape, not composition

• Unexpectedly wide A₁ receptor cavity reveals insights into allosteric drug actions

Summary

The adenosine A₁ receptor (A₁-AR) is a G-protein-coupled receptor that plays a vital role in cardiac, renal, and neuronal processes but remains poorly targeted by current drugs. We determined a 3.2 Å crystal structure of the A₁-AR bound to the selective covalent antagonist, DU172, and identified striking differences to the previously solved adenosine A_2A receptor (A_2A-AR) structure. Mutational and computational analysis of A₁-AR revealed a distinct conformation of the second extracellular loop and a wider extracellular cavity with a secondary binding pocket that can accommodate orthosteric and allosteric ligands. We propose that conformational differences in these regions, rather than amino-acid divergence, underlie drug selectivity between these adenosine receptor subtypes. Our findings provide a molecular basis for AR subtype selectivity with implications for understanding the mechanisms governing allosteric modulation of these receptors, allowing the design of more selective agents for the treatment of ischemia-reperfusion injury, renal pathologies, and neuropathic pain.