title: Targeting GSK3 from Ustilago maydis: type-II kinase inhibitors as potential antifungals.
abstract: Protein kinases are key enzymes in the complex regulation of cellular processes in almost all living organisms. For this reason, protein kinases represent attractive targets to stop the growth of eukaryotic pathogens such as protozoa and fungi. However, using kinase inhibitors to fight against these organisms bears several challenges since most of them are unselective and will also affect crucial host kinases. Here we present the X-ray structure of glycogen synthase kinase 3 from the fungal plant pathogen Ustilago maydis (UmGSK3) and its inhibition by type-II kinase inhibitors. Despite the high sequence homology between the human and the fungal variant of this vital kinase, we found substantial differences in the conformational plasticity of their active sites. Compounds that induced such conformational changes could be used to selectively inhibit the fungal kinase. This study serves as an example of how species-specific selectivity of inhibitors can be achieved by identifying and addressing the inactive state of a protein kinase. In addition to this, our study gives interesting insights into the molecular plasticity of UmGSK3 by revealing a previously unknown inactive conformation of this important kinase family.
authors.affiliation: Fakultät Chemie - Chemische Biologie, Technische Universität Dortmund, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Grütter
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Simard
authors.forename: Svenja C
authors.initials: SC
authors.lastname: Mayer-Wrangowski
authors.forename: Peter H
authors.initials: PH
authors.lastname: Schreier
authors.forename: José
authors.initials: J
authors.lastname: Pérez-Martín
authors.forename: André
authors.initials: A
authors.lastname: Richters
authors.forename: Matthäus
authors.initials: M
authors.lastname: Getlik
authors.forename: Oliver
authors.initials: O
authors.lastname: Gutbrod
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Braun
authors.forename: Michael E
authors.initials: ME
authors.lastname: Beck
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
mesh_terms: D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000008:administration & dosage*; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems / Q000379:methods*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D014588:Ustilago / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000935:Antifungal Agents; D047428:Protein Kinase Inhibitors; D038362:Glycogen Synthase Kinase 3