title: Molecular modeling of ligand-receptor interactions in GABA C receptor.
abstract: A new homology model of the GABA binding site of the GABA(C) receptor was built. Natural agonist GABA and antagonist TPMPA were docked into the receptor and molecular dynamics simulation of the complexes was performed to clarify binding poses of the ligands. It was shown that orientation of the ligand is defined by salt bridges between the ligand and the arginine (Arg104) and glutamate residues (Glu194 and Glu196) of the binding site. Different behavior and binding poses for agonist and antagonist was demonstrated by molecular dynamics simulation along with differential movement of the loop C during agonist and antagonist binding. Binding orientations of the ligands revealed that main binding forces in the GABA binding site should be electrostatic ones.
authors.affiliation: Moscow State University, Department of Chemistry, Leninskie Gory 1/3, 119991 Moscow, Russia. dmitry_o@org.chem.msu.su
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Osolodkin
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Chupakhin
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Palyulin
authors.forename: Nikolay S
authors.initials: NS
authors.lastname: Zefirov
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine; D001665:Binding Sites; D003198:Computer Simulation; D018755:GABA Agonists / Q000737:chemistry* / Q000378:metabolism; D018756:GABA Antagonists / Q000737:chemistry* / Q000378:metabolism; D018698:Glutamic Acid; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010721:Phosphinic Acids / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism; D018079:Receptors, GABA / Q000737:chemistry* / Q000378:metabolism; D055672:Static Electricity; D014443:Tyrosine; D005680:gamma-Aminobutyric Acid / Q000737:chemistry* / Q000378:metabolism
chemical_list: C101879:(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid; D018755:GABA Agonists; D018756:GABA Antagonists; D008024:Ligands; D010721:Phosphinic Acids; D011725:Pyridines; D018079:Receptors, GABA; C523978:rho1 GABA(C) receptor, human; D018698:Glutamic Acid; D014443:Tyrosine; D005680:gamma-Aminobutyric Acid; D001120:Arginine