Rules of Engagement: GPCRs and G Proteins

Research output: Contribution to journalReview ArticleResearchpeer-review

Abstract

G protein-coupled receptors (GPCRs) are a key drug target class. They account for over one-third of current pharmaceuticals, and both drugs that inhibit and promote receptor function are important therapeutically; in some cases, the same GPCR can be targeted with agonists and inhibitors, depending upon disease context. There have been major breakthroughs in understanding GPCR structure and drug binding through advances in X-ray crystallography, and membrane protein stabilization. Nonetheless, these structures have predominately been of inactive receptors bound to inhibitors. Efforts to capture structures of fully active GPCRs, in particular those in complex with the canonical, physiological transducer G protein, have been limited via this approach. Very recently, advances in cryo-electron microscopy have provided access to agonist:GPCR:G protein complex structures. These promise to revolutionize our understanding of GPCR:G protein engagement and provide insight into mechanisms of efficacy and coupling selectivity and how these might be controlled by biased agonists. Here we review what we have currently learned from the new GPCR:Gs and GPCR:Gi/o complex structures.
Original languageEnglish
Pages (from-to)73-83
Number of pages11
JournalACS Pharmacology and Translational Sciences
Volume1
Issue number2
DOIs
Publication statusPublished - 7 Sep 2018

Cite this

@article{56e554f6c20f4e7f8a3320cc845e6b3a,
title = "Rules of Engagement: GPCRs and G Proteins",
abstract = "G protein-coupled receptors (GPCRs) are a key drug target class. They account for over one-third of current pharmaceuticals, and both drugs that inhibit and promote receptor function are important therapeutically; in some cases, the same GPCR can be targeted with agonists and inhibitors, depending upon disease context. There have been major breakthroughs in understanding GPCR structure and drug binding through advances in X-ray crystallography, and membrane protein stabilization. Nonetheless, these structures have predominately been of inactive receptors bound to inhibitors. Efforts to capture structures of fully active GPCRs, in particular those in complex with the canonical, physiological transducer G protein, have been limited via this approach. Very recently, advances in cryo-electron microscopy have provided access to agonist:GPCR:G protein complex structures. These promise to revolutionize our understanding of GPCR:G protein engagement and provide insight into mechanisms of efficacy and coupling selectivity and how these might be controlled by biased agonists. Here we review what we have currently learned from the new GPCR:Gs and GPCR:Gi/o complex structures.",
author = "Alisa Glukhova and Draper-Joyce, {Christopher J} and Sunahara, {Roger K.} and Arthur Christopoulos and Wootten, {Denise L} and Sexton, {Patrick M}",
year = "2018",
month = "9",
day = "7",
doi = "10.1021/acsptsci.8b00026",
language = "English",
volume = "1",
pages = "73--83",
journal = "ACS Pharmacology and Translational Sciences",
issn = "2575-9108",
publisher = "American Chemical Society (ACS)",
number = "2",

}

Rules of Engagement: GPCRs and G Proteins. / Glukhova, Alisa; Draper-Joyce, Christopher J; Sunahara, Roger K.; Christopoulos, Arthur; Wootten, Denise L; Sexton, Patrick M.

In: ACS Pharmacology and Translational Sciences, Vol. 1, No. 2, 07.09.2018, p. 73-83.

Research output: Contribution to journalReview ArticleResearchpeer-review

TY - JOUR

T1 - Rules of Engagement: GPCRs and G Proteins

AU - Glukhova, Alisa

AU - Draper-Joyce, Christopher J

AU - Sunahara, Roger K.

AU - Christopoulos, Arthur

AU - Wootten, Denise L

AU - Sexton, Patrick M

PY - 2018/9/7

Y1 - 2018/9/7

N2 - G protein-coupled receptors (GPCRs) are a key drug target class. They account for over one-third of current pharmaceuticals, and both drugs that inhibit and promote receptor function are important therapeutically; in some cases, the same GPCR can be targeted with agonists and inhibitors, depending upon disease context. There have been major breakthroughs in understanding GPCR structure and drug binding through advances in X-ray crystallography, and membrane protein stabilization. Nonetheless, these structures have predominately been of inactive receptors bound to inhibitors. Efforts to capture structures of fully active GPCRs, in particular those in complex with the canonical, physiological transducer G protein, have been limited via this approach. Very recently, advances in cryo-electron microscopy have provided access to agonist:GPCR:G protein complex structures. These promise to revolutionize our understanding of GPCR:G protein engagement and provide insight into mechanisms of efficacy and coupling selectivity and how these might be controlled by biased agonists. Here we review what we have currently learned from the new GPCR:Gs and GPCR:Gi/o complex structures.

AB - G protein-coupled receptors (GPCRs) are a key drug target class. They account for over one-third of current pharmaceuticals, and both drugs that inhibit and promote receptor function are important therapeutically; in some cases, the same GPCR can be targeted with agonists and inhibitors, depending upon disease context. There have been major breakthroughs in understanding GPCR structure and drug binding through advances in X-ray crystallography, and membrane protein stabilization. Nonetheless, these structures have predominately been of inactive receptors bound to inhibitors. Efforts to capture structures of fully active GPCRs, in particular those in complex with the canonical, physiological transducer G protein, have been limited via this approach. Very recently, advances in cryo-electron microscopy have provided access to agonist:GPCR:G protein complex structures. These promise to revolutionize our understanding of GPCR:G protein engagement and provide insight into mechanisms of efficacy and coupling selectivity and how these might be controlled by biased agonists. Here we review what we have currently learned from the new GPCR:Gs and GPCR:Gi/o complex structures.

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DO - 10.1021/acsptsci.8b00026

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