Journal
JOURNAL OF MOLECULAR MODELING
Volume 16, Issue 10, Pages 1567-1576Publisher
SPRINGER
DOI: 10.1007/s00894-010-0678-8
Keywords
GPCRs; Tight ligand pair; Receptor activation; Molecular switches; Simulated annealing; Molecular dynamics
Categories
Funding
- Polish Ministry of Science and Higher Education [N N301 2038 33]
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Among the structurally similar guanidinonaltrindole (GNTI) compounds, 5'-GNTI is an antagonist while 6'-GNTI is an agonist of the kappa OR 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.
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