Dynamic States of the Ligand-Free Class A G Protein-Coupled Receptor Extracellular Side

Biochemistry
Qiansen ZhangHuaiyu Yang

Abstract

G protein-coupled receptors (GPCRs) make up the largest family of drug targets. The second extracellular loop (ECL2) and extracellular end of the third transmembrane helix (TM3) are basic structural elements of the GPCR ligand binding site. Currently, the disulfide bond between the two conserved cysteines in the ECL2 and TM3 is considered to be a basic GPCR structural feature. This disulfide bond has a significant effect on receptor dynamics and ligand binding. Here, molecular dynamics simulations and experimental results show that the two cysteines are distant from one another in the highest-population conformational state of ligand-free class A GPCRs and do not form a disulfide bond, indicating that the dynamics of the GPCR extracellular side are different from our conventional understanding. These surprising dynamics should have important effects on the drug binding process. On the basis of the two distinct ligand-free states, we suggest two kinetic processes for binding of ligands to GPCRs. These results challenge our commonly held beliefs regarding both GPCR structural features and ligand binding.

References

Nov 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·S S KarnikH G Khorana
Mar 3, 1999·Proceedings of the National Academy of Sciences of the United States of America·J HwaH G Khorana
Sep 25, 2002·Biochemical and Biophysical Research Communications·Junqi HeRandy A Hall
Oct 8, 2003·Current Pharmaceutical Design·Satya P KunapuliTodd M Quinton
Jan 6, 2004·Proceedings of the National Academy of Sciences of the United States of America·Lei Shi, Jonathan A Javitch
May 5, 2004·Proceedings of the National Academy of Sciences of the United States of America·A J RaderJudith Klein-Seetharaman
Jul 13, 2006·Proceedings of the National Academy of Sciences of the United States of America·Pierre SaviJean-Marc Herbert
Jan 11, 2007·The Journal of Chemical Physics·Giovanni BussiMichele Parrinello
May 16, 2007·Journal of the American Chemical Society·Ting Wang, Yong Duan
Mar 11, 2008·Thrombosis and Haemostasis·Christian Gachet
Apr 3, 2008·Nature Reviews. Drug Discovery·Malin C Lagerström, Helgi B Schiöth
Jun 20, 2008·Nature·Jung Hee ParkOliver Peter Ernst
Aug 30, 2008·Journal of Thrombosis and Haemostasis : JTH·I AlgaierI von Kügelgen
Oct 24, 2008·Biochemistry·Nathan SchmidWilfred F van Gunsteren
May 28, 2009·Proceedings of the National Academy of Sciences of the United States of America·Xiao Jie YaoBrian Kobilka
Apr 22, 2010·Proteins·Kresten Lindorff-LarsenDavid E Shaw
May 26, 2010·The Journal of Physical Chemistry. B·Jeffery B KlaudaRichard W Pastor
Nov 11, 2010·Journal of the American Chemical Society·Wenjin Li, Frauke Gräter
Jan 5, 2011·Nature Reviews. Drug Discovery·Rosamaria Lappano, Marcello Maggiolini
Jul 23, 2011·Proceedings of the National Academy of Sciences of the United States of America·Ron O DrorDavid E Shaw
Aug 2, 2011·Nature Reviews. Drug Discovery·Mathias Rask-AndersenHelgi B Schiöth
Sep 21, 2011·The Journal of Physical Chemistry. B·Samuel BockenhauerW E Moerner
Oct 29, 2011·Trends in Pharmacological Sciences·Vsevolod KatritchRaymond C Stevens
Feb 22, 2012·Science·Michael A HansonRaymond C Stevens
Feb 23, 2012·The Journal of Physical Chemistry. B·Joakim P M Jämbeck, Alexander P Lyubartsev
Mar 7, 2012·Proceedings of the National Academy of Sciences of the United States of America·Jonathan A RobertsRichard J Evans
Mar 23, 2012·Biochemical Society Transactions·Steven O Smith
Nov 13, 2012·Annual Review of Pharmacology and Toxicology·Vsevolod KatritchRaymond C Stevens
Feb 5, 2013·Cell·Rie NygaardBrian K Kobilka
Feb 15, 2013·Nature·A J VenkatakrishnanM Madan Babu
Feb 26, 2013·Nature Structural & Molecular Biology·Jianyun HuangXin-Yun Huang
May 1, 2013·The Journal of Biological Chemistry·Rabia U MalikSivaraj Sivaramakrishnan
Jul 19, 2013·Nature·Kaspar HollensteinFiona H Marshall
Sep 21, 2013·Journal of the Royal Society, Interface·Michael J WoolleyAlex C Conner
Sep 27, 2013·The Journal of Physical Chemistry. B·Maria Monica Castellanos, Coray M Colina
May 3, 2014·Nature·Jin ZhangQiang Zhao
Mar 5, 2016·Scientific Reports·Nathaniel StanleyGianni De Fabritiis
Sep 14, 2016·Chemical Reviews·Naomi R LatorracaRon O Dror

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Citations

Apr 13, 2019·Proceedings of the National Academy of Sciences of the United States of America·Bryn C TaylorRommie E Amaro

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