Structure of the Adenosine A1 Receptor Reveals the Basis for Subtype Selectivity.
Cell
; 168(5): 867-877.e13, 2017 02 23.
Article
in En
| MEDLINE
| ID: mdl-28235198
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Receptor, Adenosine A1
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Year:
2017
Type:
Article