Homology modeling of human alpha 1 beta 2 gamma 2 and house fly beta 3 GABA receptor channels and Surflex-docking of fipronil.
To further explore the mechanism of selective binding of the representative gamma-aminobutyric acid receptors (GABARs) noncompetitive antagonist (NCA) fipronil to insect over mammalian GABARs, three-dimensional models of human alpha 1 beta 2 gamma 2 and house fly beta 3 GABAR were generated by homology modeling, using the cryo-electron microscopy structure of the nicotinic acetylcholine receptor (nAChR) of Torpedo marmorata as a template. Fipronil was docked into the putative binding site of the human alpha 1 beta 2 gamma 2 and house fly beta 3 receptors by Surflex-docking, and the calculated docking energies are in agreement with experimental results. The GABA receptor antagonist fipronil exhibited higher potency with house fly beta 3 GABAR than with human alpha 1 beta 2 gamma 2 GABAR. Furthermore, analyses of Surflex-docking suggest that the H-bond interaction of fipronil with Ala2 and Thr6 in the second transmembrane segment (TM2) of these GABARs plays a relatively important role in ligand selective binding. The different subunit assemblies of human alpha 1 beta 2 gamma 2 and house fly beta 3 GABARs may result in differential selectivity for fipronil.
Cheng
Jin
J
School of Chemical Engineering & Pharmacy, Key Laboratory for Green Chemical Process of Ministry of Education, Wuhan Institute of Technology, Wuhan, 430073, People's Republic of China.
Ju
Xiu-Lian
XL
Chen
Xiang-Yang
XY
Liu
Gen-Yan
GY
D000409:Alanine / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D020285:Cryoelectron Microscopy; D058787:GABA-A Receptor Antagonists; D006793:Houseflies; D006801:Humans; D007306:Insecticides / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011720:Pyrazoles / Q000737:chemistry*; D011963:Receptors, GABA-A / Q000737:chemistry*; D011978:Receptors, Nicotinic / Q000737:chemistry; D013912:Threonine / Q000737:chemistry; D014101:Torpedo
D058787:GABA-A Receptor Antagonists; C546240:GABRA1 protein, human; C495710:GABRB2 protein, human; C546273:GABRB3 protein, human; C546279:GABRG2 protein, human; D007306:Insecticides; D011720:Pyrazoles; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic; D013912:Threonine; D000409:Alanine; C082360:fipronil