Investigating allosteric effects on the functional dynamics of β2-adrenergic ternary complexes with enhanced-sampling simulations

Chemical Science
Noureldin SalehTimothy Clark

Abstract

Signalling by G-protein coupled receptors usually occurs via ternary complexes formed under cooperative binding between the receptor, a ligand and an intracellular binding partner (a G-protein or β-arrestin). While a global rational for allosteric effects in ternary complexes would be of great help in designing ligands with specific effects, the paucity of structural data for ternary complexes with β-arrestin, together with the intrinsic difficulty of characterizing the dynamics involved in the allosteric coupling, have hindered the efforts to devise such a model. Here we have used enhanced-sampling atomistic molecular-dynamics simulations to investigate the dynamics and complex formation mechanisms of both β-arrestin- and Gs-complexes with the β2-adrenergic receptor (ADRB2) in its apo-form and in the presence of four small ligands that exert different allosteric effects. Our results suggest that the structure and dynamics of arrestin-ADRB2 complexes depend strongly on the nature of the small ligands. The complexes exhibit a variety of different coupling orientations in terms of the depth of the finger loop in the receptor and activation states of ADRB2. The simulations also allow us to characterize the cooperativity between th...Continue Reading

References

Jan 25, 1996·Nature·D G LambrightP B Sigler
Nov 20, 1997·The Journal of Biological Chemistry·V V GurevichJ J Onorato
Sep 25, 2002·Proceedings of the National Academy of Sciences of the United States of America·Alessandro Laio, Michele Parrinello
Oct 11, 2007·Proceedings of the National Academy of Sciences of the United States of America·James W WislerRobert J Lefkowitz
Jan 1, 2009·Annual Reports in Computational Chemistry·Alan Grossfield, Daniel M Zuckerman
Jul 31, 2010·Journal of the American Chemical Society·Daniel WackerRaymond C Stevens
Dec 25, 2010·Trends in Molecular Medicine·Erin J WhalenRobert J Lefkowitz
Jan 14, 2011·Nature·Søren G F RasmussenBrian K Kobilka
Jul 21, 2011·Nature·Søren G F RasmussenBrian K Kobilka
Jul 23, 2011·Proceedings of the National Academy of Sciences of the United States of America·Ron O DrorDavid E Shaw
Oct 28, 2011·Proceedings of the National Academy of Sciences of the United States of America·Ron O DrorDavid E Shaw
Mar 13, 2012·Journal of Chemical Information and Modeling·Zhiwei FengYouyong Li
Jun 20, 2013·Proceedings of the National Academy of Sciences of the United States of America·Yinglong MiaoJ Andrew McCammon
Nov 22, 2013·Nature·Andrew C KruseBrian K Kobilka
Apr 1, 2014·Current Opinion in Cell Biology·James W WislerRobert J Lefkowitz
Jul 22, 2014·Journal of the American Chemical Society·Alexander S RosePeter W Hildebrand
Dec 6, 2014·ChemistryOpen·Carolin SchaabPeter Gmeiner
Dec 17, 2014·Accounts of Chemical Research·Andrea CavalliFrancesco L Gervasio
Aug 8, 2015·Nature·Weijiao HuangBrian K Kobilka
Jan 13, 2016·Journal of Chemical Theory and Computation·Dimitar V PachovHenry van den Bedem
Feb 16, 2016·Chemical Reviews·Jingjing Guo, Huan-Xiang Zhou
Feb 19, 2016·Chemical Reviews·Elena PapaleoRuth Nussinov
May 18, 2016·Angewandte Chemie·Noureldin SalehTimothy Clark
Jul 1, 2016·Nature·Brian T DeVreeRoger K Sunahara
Jul 28, 2016·Nature Communications·Harald HübnerPeter Gmeiner
Nov 9, 2016·Nature Communications·Punita KumariArun K Shukla

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Citations

Sep 26, 2019·Physical Chemistry Chemical Physics : PCCP·Noureldin SalehKresten Lindorff-Larsen
Jul 8, 2017·Beilstein Journal of Organic Chemistry·Timothy Clark
Jun 24, 2020·Proceedings of the National Academy of Sciences of the United States of America·Giulio MattediFrancesco Luigi Gervasio
Jun 19, 2018·Frontiers in Pharmacology·Noureldin SalehPatrick Scheerer
Dec 5, 2019·Frontiers in Oncology·Ruth NussinovHyunbum Jang
Oct 7, 2020·Proceedings of the National Academy of Sciences of the United States of America·Dibyendu MondalArieh Warshel
Oct 21, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Anette Kaiser, Irene Coin
Jun 10, 2021·The Journal of Physical Chemistry. B·Humanath Poudel, David M Leitner
Aug 27, 2019·Journal of Chemical Information and Modeling·Passainte IbrahimTimothy Clark
Jul 10, 2019·The Journal of Physical Chemistry. B·Jinan Wang, Yinglong Miao
Nov 23, 2021·Journal of Chemical Information and Modeling·Jianfang ChenXuemei Pu

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Methods Mentioned

BETA
nucleotide exchange
X-ray
fluorescence spectroscopy

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