title: Generation and evaluation of a homology model of PfGSK-3.
abstract: Plasmodial GSK-3 is a potential new target for malaria therapy. For a structure-based design project, the three-dimensional information of the designated target is needed. Unfortunately, experimental structure data for plasmodial GSK-3 is not yet available. Homology building can be used to generate such three-dimensional structure data using structure information of a homologous protein. GSK-3 possesses a very flexible ATP-binding site, a fact reflected in the variety of X-ray structures of the human GSK-3beta which are deposited in the protein data base and are crystallized with different ligands. We used ten different HsGSK-3beta templates for the model building of plasmodial GSK-3 and generated 200 models for each template with different modeling protocols. The quality of the models was evaluated with different tools. The results of these evaluations were used to calculate a rank-by-rank consensus score. The top models of this were used to compile an ensemble of PfGSK-3 models that reflect the flexibility of the ATP-binding site and that will be used for the structure-based design of potential ATP-binding site inhibitors of PfGSK-3.
authors.affiliation: Institute of Pharmacy, University of Hamburg, Hamburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kruggel
authors.forename: Thomas
authors.initials: T
authors.lastname: Lemcke
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D001665:Binding Sites; D016503:Drug Delivery Systems; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000201:enzymology; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000201:enzymology*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
chemical_list: D000962:Antimalarials; D000255:Adenosine Triphosphate; D038362:Glycogen Synthase Kinase 3