Journal
CELL
Volume 168, Issue 5, Pages 867-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2017.01.042
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Funding
- National Health and Medical Research Council of Australia (NHMRC) [APP1055134, APP1084246]
- Australian Endeavour Scholarship and Fellowship
- Australian Research Council (ARC) Discovery Early Career Researcher Award (DECRA)
- Australian Postgraduate Award
- Australian Cancer Therapeutics scholarship
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The adenosine A(1) receptor (A(1)-AR) is a G-proteincoupled receptor that plays a vital role in cardiac, renal, and neuronal processes but remains poorly targeted by current drugs. We determined a 3.2 angstrom crystal structure of the A(1)-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 A(1)-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.
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