title: Full and partial agonism of ionotropic glutamate receptors indicated by molecular dynamics simulations.
abstract: Ionotropic glutamate receptors (iGluRs) are synaptic proteins that facilitate signal transmission in the central nervous system. Extracellular iGluR cleft closure is linked to receptor activation; however, the mechanism underlying partial agonism is not entirely understood. Full agonists close the bilobed ligand-binding domain (LBD), while antagonists prevent closure; the transmembrane ion channel either opens or stays closed, respectively. Although some bulky partial agonists produce intermediate iGluR-LBD closure, the available crystal structures also imply that the cleft can be shut with certain partial agonists. Recently, we have shown that the iGluR-LBD closure stage can be recreated by inserting a ligand into the closed cleft and simulating the ligand-receptor complex with molecular dynamics. Our simulations indicate that partial agonist binding does not necessarily prevent full receptor cleft closure; instead, it destabilizes cleft closure. Interdomain hydrogen bonds were studied thoroughly, and one hydrogen bond, in particular, was consistently disrupted by bound partial agonists. Accordingly, the simulation protocol presented here can be used to categorize compounds in silico as partial or full agonists for iGluRs.
authors.affiliation: Department of Biological and Environmental Science, P.O. Box 35, University of Jyväskylä , FI-40014, Finland.
authors.forename: Pekka A
authors.initials: PA
authors.lastname: Postila
authors.forename: Mikko
authors.initials: M
authors.lastname: Ylilauri
authors.forename: Olli T
authors.initials: OT
authors.lastname: Pentikäinen
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D058468:Receptors, Ionotropic Glutamate / Q000819:agonists* / Q000737:chemistry
chemical_list: D008024:Ligands; D058468:Receptors, Ionotropic Glutamate