Structure of the adenosine A1 receptor reveals the basis for subtype selectivity

Research output: Contribution to journalArticleResearchpeer-review

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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.

Original languageEnglish
Pages (from-to)867-877.e13
JournalCell
Volume168
Issue number5
DOIs
Publication statusPublished - 23 Feb 2017

Keywords

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

Cite this

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title = "Structure of the adenosine A1 receptor reveals the basis for subtype selectivity",
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 {\AA} 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.",
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Structure of the adenosine A1 receptor reveals the basis for subtype selectivity. / Glukhova, Alisa; Thal, David M; Nguyen, Anh T; Vecchio, Liz; Jorg, Manuela; Scammells, Peter J; May, Lauren T; Sexton, Patrick M; Christopoulos, Arthur.

In: Cell, Vol. 168, No. 5, 23.02.2017, p. 867-877.e13.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Glukhova, Alisa

AU - Thal, David M

AU - Nguyen, Anh T

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AU - Jorg, Manuela

AU - Scammells, Peter J

AU - May, Lauren T

AU - Sexton, Patrick M

AU - Christopoulos, Arthur

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AB - 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.

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