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Cell. 2017 Feb 23;168(5):867-877.e13. doi: 10.1016/j.cell.2017.01.042.

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

Author information

1
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
2
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
3
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. Electronic address: patrick.sexton@monash.edu.
4
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. Electronic address: arthur.christopoulos@monash.edu.

Abstract

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 A2A receptor (A2A-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.

KEYWORDS:

G-protein-coupled receptor; adenosine; allosteric modulation; cardiovascular disease; crystallography; drug design; drug discovery; ischemia-reperfusion; neuropathic pain; structural biology

PMID:
28235198
DOI:
10.1016/j.cell.2017.01.042
[Indexed for MEDLINE]
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