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

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",
number = "7711",

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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

TY - JOUR

T1 - Structure of the adenosine-bound human adenosine A1 receptor-Gi complex

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

Y1 - 2018/6/20

N2 - 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.

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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