Catalytic loop motion in human glutathione synthetase: A molecular modeling approach.
Conformational changes of three flexible loops (G, A, and S) in human glutathione synthetase (hGS) arise to accommodate the substrates inside the active site. The crystal structure of hGS, a member of the ATP-grasp superfamily, has been reported only for the product-enzyme complex. To study the function of the hGS loops, molecular dynamics simulations are performed on three different conformational models: unbound enzyme, reactant-enzyme, and product-enzyme complex of hGS. The conformational changes among the three models are analyzed and the roles of the loops during the catalytic process are described. The modeled structures of hGS show that the central portions of the G- and A-loop have a double role in the reactant complex conformation: they bind the substrates and simultaneously interact with each other through an extensive network of hydrogen bonds. The present study proposes that these favorable loop-ligand and loop-loop interactions are required for opening and closing of the active site of hGS. Additionally, this research identifies important amino acid residues and explains their function within the catalytic loops of hGS.
Dinescu
Adriana
A
Department of Chemistry, Center for Advanced Scientific Computing and Modeling (CASCaM), University of North Texas, Denton, TX 76203, USA.
Anderson
Mary E
ME
Cundari
Thomas R
TR
D000595:Amino Acid Sequence; D002384:Catalysis; D003198:Computer Simulation; D004789:Enzyme Activation; D005981:Glutathione Synthase / Q000737:chemistry* / Q000648:ultrastructure*; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009038:Motion; D020539:Sequence Analysis, Protein / Q000379:methods*
D005981:Glutathione Synthase