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

Christopher J. Draper-Joyce, Maryam Khoshouei, David M. Thal, Yi Lynn Liang, Anh T.N. Nguyen, Sebastian G.B. Furness, Hariprasad Venugopal, Jo Anne Baltos, Jürgen M. Plitzko, Radostin Danev, Wolfgang Baumeister, Lauren T. May, Denise Wootten, Patrick M. Sexton, Alisa Glukhova, Arthur Christopoulos

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)559-565
Number of pages7
JournalNature
Volume558
Issue number7711
DOIs
Publication statusPublished - 20 Jun 2018

Cite this

@article{96e06121ab064f77ab6e47ac2511185f,
title = "Structure of the adenosine-bound human adenosine A1 receptor-Gi complex",
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 {\AA} 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 {\AA} 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.",
author = "Draper-Joyce, {Christopher J.} and Maryam Khoshouei and Thal, {David M.} and Liang, {Yi Lynn} and Nguyen, {Anh T.N.} and Furness, {Sebastian G.B.} and Hariprasad Venugopal and Baltos, {Jo Anne} and Plitzko, {J{\"u}rgen M.} and Radostin Danev and Wolfgang Baumeister and May, {Lauren T.} and Denise Wootten and Sexton, {Patrick M.} and Alisa Glukhova and Arthur Christopoulos",
year = "2018",
month = "6",
day = "20",
doi = "10.1038/s41586-018-0236-6",
language = "English",
volume = "558",
pages = "559--565",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
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Structure of the adenosine-bound human adenosine A1 receptor-Gi complex. / Draper-Joyce, Christopher J.; Khoshouei, Maryam; Thal, David M.; Liang, Yi Lynn; Nguyen, Anh T.N.; Furness, Sebastian G.B.; Venugopal, Hariprasad; Baltos, Jo Anne; Plitzko, Jürgen M.; Danev, Radostin; Baumeister, Wolfgang; May, Lauren T.; Wootten, Denise; Sexton, Patrick M.; Glukhova, Alisa; Christopoulos, Arthur.

In: Nature, Vol. 558, No. 7711, 20.06.2018, p. 559-565.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Draper-Joyce, Christopher J.

AU - Khoshouei, Maryam

AU - Thal, David M.

AU - Liang, Yi Lynn

AU - Nguyen, Anh T.N.

AU - Furness, Sebastian G.B.

AU - Venugopal, Hariprasad

AU - Baltos, Jo Anne

AU - Plitzko, Jürgen M.

AU - Danev, Radostin

AU - Baumeister, Wolfgang

AU - May, Lauren T.

AU - Wootten, Denise

AU - Sexton, Patrick M.

AU - Glukhova, Alisa

AU - Christopoulos, Arthur

PY - 2018/6/20

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AB - 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.

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