Journal of Molecular Modeling

, Volume 16, Issue 10, pp 1567–1576 | Cite as

Study of a structurally similar kappa opioid receptor agonist and antagonist pair by molecular dynamics simulations

  • Michal Kolinski
  • Slawomir Filipek
Original Paper


Among the structurally similar guanidinonaltrindole (GNTI) compounds, 5′-GNTI is an antagonist while 6′-GNTI is an agonist of the κOR opioid receptor. To explore how a subtle alteration of the ligand structure influences the receptor activity, we investigated two concurrent processes: the final steps of ligand binding at the receptor binding site and the initial steps of receptor activation. To trace these early activation steps, the membranous part of the receptor was built on an inactive receptor template while the extracellular loops were built using the ab initio CABS method. We used the simulated annealing procedure for ligand docking and all-atom molecular dynamics simulations to determine the immediate changes in the structure of the ligand–receptor complex. The binding of an agonist, in contrast to an antagonist, induced the breakage of the “3–7 lock” between helices TM3 and TM7. We also observed an action of the extended rotamer toggle switch which suggests that those two switches are interdependent.


Molecular dynamics simulations revealed different properties of the agonist 6'-GNTI and the antagonist 5'-GNTI of the κOR opioid receptor. Different binding mode of the agonist induced break of 3-7 lock and action of rotamer toggle switch


GPCRs Tight ligand pair Receptor activation Molecular switches Simulated annealing Molecular dynamics 



The work was supported by the Polish Ministry of Science and Higher Education (Grant no. N N301 2038 33). M. Kolinski acknowledges the School of Molecular Medicine for a stipend that supported his Ph.D. study.

Supplementary material

894_2010_678_MOESM1_ESM.mpg (5.6 mb)
Animation 1 The representative parts of molecular dynamics simulations of complexes of 5′-GNTI (an antagonist, shown in green) with model 1 of κOR. The distance between residues D3.32(138) and Y7.43(320) (the 3–7 lock) is shown as a white dashed line (MPG 5738 kb)
894_2010_678_MOESM2_ESM.mpg (5.8 mb)
Animation 2 The representative parts of molecular dynamics simulations of complexes of 5′-GNTI (an antagonist, shown in green) with model 2 of κOR. The distance between residues D3.32(138) and Y7.43(320) (the 3–7 lock) is shown as a white dashed line (MPG 5929 kb)
894_2010_678_MOESM3_ESM.mpg (5.4 mb)
Animation 3 3–7 lock breaking during molecular dynamics simulations of complexes of 6′-GNTI (an agonist, shown in orange) with model 1 of κOR. The distance between residues D3.32(138) and Y7.43(320) (the 3–7 lock) is shown as a white dashed line (MPG 5551 kb)
894_2010_678_MOESM4_ESM.mpg (5.4 mb)
Animation 4 3–7 lock breaking during molecular dynamics simulations of complexes of 6′-GNTI (an agonist, shown in orange) with model 2 of κOR. The distance between residues D3.32(138) and Y7.43(320) (the 3–7 lock) is shown as a white dashed line (MPG 5557 kb)


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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.International Institute of Molecular and Cell BiologyWarsawPoland
  2. 2.Faculty of ChemistryWarsaw UniversityWarsawPoland

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