Ligands and signaling proteins govern the conformational landscape explored by a G protein-coupled receptor.

Proceedings of the National Academy of Sciences of the United States of America
Sophie MaryJean-Louis Banères

Abstract

The dynamic character of G protein-coupled receptors is essential to their function. However, the details of how ligands stabilize a particular conformation to selectively activate a signaling pathway and how signaling proteins affect this conformational repertoire remain unclear. Using a prototypical peptide-activated class A G protein-coupled receptor (GPCR), the ghrelin receptor, reconstituted as a monomer into lipid discs and labeled with a fluorescent conformational reporter, we demonstrate that ligand efficacy and functional selectivity are directly related to different receptor conformations. Of importance, our data bring direct evidence that distinct effector proteins affect the conformational landscape of the ghrelin receptor in different ways. Whereas G proteins affect the balance between active and inactive receptor substates in favor of the active state, agonist-induced arrestin recruitment is accompanied by a marked change in the structural features of the receptor that adopt a conformation different from that observed in the absence of arrestin. In contrast to G proteins and arrestins, μ-AP2 has no significant effect on the organization of the transmembrane core of the receptor. Such a modulation of a GPCR conform...Continue Reading

References

Jul 5, 2001·Proceedings of the National Academy of Sciences of the United States of America·G PelegR N Zare
Mar 21, 2003·Journal of Medicinal Chemistry·Vincent GuerlavaisJean Martinez
Oct 16, 2003·The Journal of Biological Chemistry·Gayathri SwaminathBrian K Kobilka
Apr 3, 2004·Trends in Pharmacological Sciences·Birgitte Holst, Thue W Schwartz
Sep 24, 2004·The Journal of Biological Chemistry·Birgitte HolstThue W Schwartz
Mar 19, 2005·The Journal of Biological Chemistry·Jean-Louis BanèresJoel Bockaert
Jun 27, 2006·Nature Chemical Biology·Xiaojie YaoBrian Kobilka
May 28, 2009·Proceedings of the National Academy of Sciences of the United States of America·Xiao Jie YaoBrian Kobilka
Oct 13, 2009·Endocrinology·Pia Steen PetersenBirgitte Holst
Jul 17, 2010·Annals of the New York Academy of Sciences·Masayasu Kojima, Kenji Kangawa
Oct 14, 2010·Physiology·Xavier Deupi, Brian K Kobilka
Jan 14, 2011·Nature·Søren G F RasmussenBrian K Kobilka
Jan 14, 2011·Nature·Daniel M RosenbaumBrian K Kobilka
Jul 5, 2011·Current Opinion in Structural Biology·Xavier Deupi, Jörg Standfuss
Jul 21, 2011·Nature·Søren G F RasmussenBrian K Kobilka
Aug 23, 2011·Nature Chemical Biology·Alem W KahsaiRobert J Lefkowitz
Aug 27, 2011·Methods in Molecular Biology·Louis M Luttrell, Terry P Kenakin

❮ Previous
Next ❯

Citations

Mar 13, 2013·Proceedings of the National Academy of Sciences of the United States of America·Denise WoottenPatrick M Sexton
May 21, 2013·Annual Review of Neuroscience·Krzysztof Palczewski, Tivadar Orban
Oct 11, 2013·Proceedings of the National Academy of Sciences of the United States of America·Sadani N CoorayMauro Perretti
Oct 25, 2013·Proceedings of the National Academy of Sciences of the United States of America·János G Filep
Jul 22, 2014·Trends in Pharmacological Sciences·Terry Kenakin
Jun 17, 2014·The Journal of Physiology·Nevin A Lambert, Jonathan A Javitch
Feb 10, 2016·Chemical Reviews·Terry Kenakin
Jan 31, 2016·Archives of Pharmacal Research·Ji Young ParkKa Young Chung
May 8, 2014·The Journal of Membrane Biology·Sophie MaryJean-Louis Banères
Jan 9, 2013·Biotechnology and Bioengineering·Christian BergerDaniel Huster
Jan 30, 2013·Biochemical Society Transactions·Sophie MaryJean-Louis Banères
Sep 24, 2013·Biochimica Et Biophysica Acta·Rajashri SridharanMark E Dumont
Apr 1, 2014·Current Opinion in Cell Biology·James W WislerRobert J Lefkowitz
Dec 3, 2014·Trends in Biochemical Sciences·Arun K ShuklaEshan Ghosh
Jul 9, 2014·Frontiers in Immunology·Anne SteenMette M Rosenkilde
Oct 22, 2016·Cell·Sebastian George Barton FurnessPatrick Michael Sexton
Dec 31, 2016·Biomolecules & Therapeutics·Nguyen Minh DucKa Young Chung
Mar 10, 2017·Expert Opinion on Drug Discovery·Terry Kenakin
Apr 12, 2017·International Journal of Molecular Sciences·Gustav ColldénTimo D Müller
Jan 6, 2018·Nature Reviews. Drug Discovery·Jeffrey S SmithSudarshan Rajagopal
Sep 13, 2015·The Journal of Biological Chemistry·Céline M'KadmiJacky Marie
Dec 19, 2014·Circulation Research·Maik DrechslerOliver Soehnlein
Nov 10, 2018·Nature Reviews. Drug Discovery·Ichio ShimadaKurt Wüthrich
Jul 19, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Valerie T RamirezHarriët Schellekens
Sep 22, 2012·British Journal of Pharmacology·Terry Kenakin
Dec 1, 2012·Molecular Pharmacology·Alaa Abdul-RidhaArthur Christopoulos
Jul 4, 2015·Molecular Pharmacology·Terry Kenakin
Jul 26, 2014·Molecular Pharmacology·Arthur Christopoulos
Aug 12, 2014·Pharmacological Reviews·Brid Callaghan, John B Furness
Sep 28, 2014·The Journal of Biological Chemistry·Tama EvronLarry S Barak
Feb 13, 2020·Endocrinology·Morten Adler Hedegaard, Birgitte Holst
Apr 11, 2018·Proceedings of the National Academy of Sciences of the United States of America·Marjorie DamianJean-Louis Banères
Mar 29, 2014·The Journal of Biological Chemistry·Ryan T StrachanRobert J Lefkowitz

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.