title: The binding mode of picrotoxinin in GABAA-ρreceptors: Insight into the subunit's selectivity in the transmembrane domain.
abstract: The channel blocker picrotoxinin has been studied with GABAA-ρ1and GABAA-ρ2homology models based on the GluCl crystal structure. Picrotoxinin is tenfold more potent for GABAA-ρ2than for GABAA-ρ1homomeric channels. This intra-subunit selectivity arises from the unconserved residues at the 2' sites, which are the essential molecular basis for both the binding and potency of picrotoxinin. The serine residues at the 2' positions of the ρ2 channel are predicted to form multiple hydrogen bonds and hydrophobic interactions with picrotoxinin, whereas the proline residues in the 2' positions of ρ1 channels are predicted to form only hydrophobic contacts with picrotoxinin. However, although the studied ρ1 P2'G, A, and V models form no hydrogen bonds with picrotoxinin, they may participate in several hydrophobic interactions, and the ligand may have distinctive binding modes with GABAA-ρmutant channels. Picrotoxinin has a lower Emodel value with ρ2 than ρ1 homomeric models (-47Kcal/mol and -36Kcal/mol, respectively), suggesting that picrotoxin blocks the pores of the ρ2 channels more effectively.
authors.affiliation: The Division of Biology and Biomedical Sciences, Washington University in St Louis, United States. Electronic address: moawiahnaffaa@wustl.edu.
authors.forename: Moawiah M
authors.initials: MM
authors.lastname: Naffaa
authors.affiliation: Dept. of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
authors.forename: Abdul
authors.initials: A
authors.lastname: Samad
mesh_terms: D001665:Binding Sites; D002462:Cell Membrane; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008024:Ligands; D008954:Models, Biological; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010852:Picrotoxin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000072417:Protein Domains; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D054830:Sesterterpenes
chemical_list: D008024:Ligands; D010852:Picrotoxin; D011963:Receptors, GABA-A; D054830:Sesterterpenes; C022961:picrotoxinin
keywords: GABAA-ρ receptors; Homology modeling and selectivity; Picrotoxinin