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Nature. 2018 Jun;558(7711):559-563. doi: 10.1038/s41586-018-0236-6. Epub 2018 Jun 20.

Structure of the adenosine-bound human adenosine A1 receptor-Gi complex.

Author information

1
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
2
Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.
3
Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
4
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
5
School of Pharmacy, Fudan University, Shanghai, China.
6
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. patrick.sexton@monash.edu.
7
School of Pharmacy, Fudan University, Shanghai, China. patrick.sexton@monash.edu.
8
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. alisa.glukhova@monash.edu.
9
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. arthur.christopoulos@monash.edu.

Abstract

The class A adenosine A1 receptor (A1R) is a G-protein-coupled receptor that preferentially couples to inhibitory Gi/o heterotrimeric G proteins, has been implicated in numerous diseases, yet remains poorly targeted. Here we report the 3.6 Å structure of the human A1R in complex with adenosine and heterotrimeric Gi2 protein determined by Volta phase plate cryo-electron microscopy. Compared to inactive A1R, there is contraction at the extracellular surface in the orthosteric binding site mediated via movement of transmembrane domains 1 and 2. At the intracellular surface, the G protein engages the A1R primarily via amino acids in the C terminus of the Gαi α5-helix, concomitant with a 10.5 Å outward movement of the A1R transmembrane domain 6. Comparison with the agonist-bound β2 adrenergic receptor-Gs-protein complex reveals distinct orientations for each G-protein subtype upon engagement with its receptor. This active A1R structure provides molecular insights into receptor and G-protein selectivity.

PMID:
29925945
DOI:
10.1038/s41586-018-0236-6
[Indexed for MEDLINE]

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