Paper Citing NAMD - Abstract
Sencanski, Milan; Dosen-Micovic, Ljiljana
In Silico Study of the Structurally Similar ORL1 Receptor Agonist and Antagonist Pairs Reveal Possible Mechanism of Receptor Activation
PROTEIN JOURNAL, 33:231-242, JUN 2014
An opioid receptor like (ORL1) receptor is a member of a family of G-protein coupled receptors. It is a new pharmaceutical target with broad therapeutic potential in the regulation of important biological functions such as nociception, mood disorders, drug abuse, learning or cardiovascular control. The crystal structure of this receptor in complex with an antagonist was determined recently (PDB ID: 4EA3). By removing the ligand and subjecting the empty receptor to molecular dynamics simulation in a solvated lipid membrane we obtained an optimized ORL1 receptor structure which could be used in a subsequent docking study of two structurally similar agonist-antagonist ligand pairs. Ligands were docked to the empty ORL1 receptor (with and without the third intracellular loop, IC3) in different orientations, and the resulting complexes were monitored during molecular dynamics simulation in order to see how the subtle differences in structure of agonists and antagonists might affect ligand-receptor interactions and trigger receptor activation. It was established that agonists and antagonists bound to the same, relatively large, binding site in the receptor, created by residues from transmembrane helices TM2, TM3, TM5, TM6 and TM7 and close to the extra cellular end of the receptor bundle. The key difference between these two types of ligands is interaction with residue Val283(6.55) and a flexibility of ligand molecules. Ligands that cannot easily avoid this interaction will initiate movement of the intracellular end of TM6 (by a mechanism which involves Met134(3.36) and several aminoacids of TM5) and possibly activate the receptor when assisted by G-protein.
