Study of a structurally similar kappa opioid receptor agonist and antagonist pair by molecular dynamics simulations
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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.
KeywordsGPCRs 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.
- 12.Strange PG (2008) Signaling mechanisms of GPCR ligands. Curr Opin Drug Discov Dev 11:196–202Google Scholar
- 25.Sanchez R, Sali A (1997) Evaluation of comparative protein structure modeling by MODELLER-3. Proteins Suppl 1:50–58Google Scholar
- 27.Kolinski A (2004) Protein modeling and structure prediction with a reduced representation. Acta Biochim Pol 51:349–371Google Scholar