Determinants of Orexin Receptor Binding and Activation-A Molecular Dynamics Study

The Journal of Physical Chemistry. B
Lasse KarhuHenri Xhaard

Abstract

We assess the stability of two previously suggested binding modes for the neuropeptide orexin-A in the OX2 receptor through extensive molecular dynamics simulations. As the activation determinants of the receptor remain unknown, we simulated an unliganded receptor and two small-molecular ligands, the antagonist suvorexant and the agonist Nag26 for comparison. Each system was simulated in pure POPC membrane as well as in the 25% cholesterol-POPC membrane. In total, we carried out 36 μs of simulations. Through this set of simulations, we report a stable binding mode for the C-terminus of orexin-A. In addition, we suggest interactions that would promote orexin receptor activation, as well as others that would stabilize the inactive state.

References

Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Dec 3, 1999·European Journal of Biochemistry·J H LeeW Lee
Jan 1, 2000·Lancet·S NishinoE Mignot
Nov 23, 2000·Physical Review. E, Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics·G PabstP Laggner
Mar 27, 2001·Bioorganic & Medicinal Chemistry Letters·J G DarkerJ C Jerman
Oct 24, 2002·Journal of Computational Chemistry·Araz JakalianChristopher I Bayly
Dec 7, 2002·Bioorganic & Medicinal Chemistry Letters·Shuichi AsahiHajime Morishima
Feb 28, 2003·The Journal of Pharmacology and Experimental Therapeutics·Sylwia AmmounJyrki P Kukkonen
Jun 5, 2003·Proteins·Rong ChenZhiping Weng
Oct 28, 2003·Proteins·Li LiZhiping Weng
Oct 14, 2004·Journal of Biochemistry and Molecular Biology·Hai-Young KimWeontae Lee
Jan 24, 2006·Journal of Peptide Science : an Official Publication of the European Peptide Society·Tomoyo TakaiTakahisa Ikegami
Apr 11, 2006·The Journal of Membrane Biology·Norbert KucerkaJohn F Nagle
Jun 16, 2007·The Journal of Physical Chemistry. B·Siewert J MarrinkAlex H de Vries
Jan 25, 2008·Nature Reviews. Molecular Cell Biology·Gerrit van MeerGerald W Feigenson
Mar 21, 2008·Journal of Computational Chemistry·Sunhwan JoWonpil Im
Dec 19, 2008·Journal of Computational Chemistry·William J AllenDavid R Bevan
Apr 22, 2010·Proteins·Kresten Lindorff-LarsenDavid E Shaw
Nov 3, 2010·Annual Review of Pharmacology and Toxicology·Thomas E Scammell, Christopher J Winrow
Jun 18, 2011·European Journal of Pharmacology·Da-Thao TranSteven W Sutton
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
Dec 22, 2012·Physical Chemistry Chemical Physics : PCCP·Tiago Mendes FerreiraDaniel Topgaard
Jan 30, 2013·Biochemical Society Transactions·Hugo Gutiérrez-de-TeránDavid Rodríguez
Aug 2, 2013·British Journal of Pharmacology·J P Kukkonen, C S Leonard
Nov 22, 2013·Nature·Andrew C KruseBrian K Kobilka
Apr 8, 2014·ACS Medicinal Chemistry Letters·Nadezhda A GermanYanan Zhang
Aug 19, 2014·Journal of Computational Chemistry·Emilia L WuWonpil Im
Dec 5, 2014·Molecular Pharmacology·Arnault MassinkAdriaan P IJzerman
Dec 30, 2014·Trends in Pharmacological Sciences·Vignir IsbergDavid E Gloriam
May 10, 2015·BMC Structural Biology·Lasse KarhuHenri Xhaard
Aug 8, 2015·Nature·Weijiao HuangBrian K Kobilka

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