title: Structural characterization of the PPIase domain of FKBP51, a cochaperone of human Hsp90.
abstract: Steroid hormone receptors are key components of mammalian stress and sex hormone systems. Many of them rely on the Hsp90 chaperone system for full function and are further fine-tuned by Hsp90-associated peptidyl-prolyl isomerases such as FK506-binding proteins 51 and 52. FK506-binding protein 51 (FKBP51) has been shown to reduce glucocorticoid receptor signalling and has been genetically associated with human stress resilience and with numerous psychiatric disorders. The peptidyl-prolyl isomerase domain of FKBP51 contains a high-affinity binding site for the natural products FK506 and rapamycin and has further been shown to convey most of the inhibitory activity on the glucocorticoid receptor. FKBP51 has therefore become a prime new target for the treatment of stress-related affective disorders that could be amenable to structure-based drug design. Here, a series of high-resolution structures of the peptidyl-prolyl isomerase domain of FKBP51 as well as a cocrystal structure with the prototypic ligand FK506 are described. These structures provide a detailed picture of the drug-binding domain of FKBP51 and the molecular binding mode of its ligand as a starting point for the rational design of improved inhibitors.
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany. bracher@biochem.mpg.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Bracher
authors.forename: Christian
authors.initials: C
authors.lastname: Kozany
authors.forename: Ann Katrin
authors.initials: AK
authors.lastname: Thost
authors.forename: Felix
authors.initials: F
authors.lastname: Hausch
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D019696:Peptidylprolyl Isomerase / Q000737:chemistry; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D016559:Tacrolimus / Q000737:chemistry / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000099159:Tacrolimus Binding Protein 5
chemical_list: D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5