Structural characterization of the PPIase domain of FKBP51, a cochaperone of human Hsp90

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 like the FK506 binding proteins 51 and 52. FKBP51 has been shown to reduce glucocorticoid receptor signaling and has been genetically associated with the 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 we describe a series of high resolution structures for the peptidyl prolyl isomerase domain of FKBP51 as well as a cocrystal structure with the prototypic ligand FK506. 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.