Bracher Andreas, Kozany Christian, Thost Ann Katrin, Hausch Felix
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
Acta Crystallogr D Biol Crystallogr. 2011 Jun;67(Pt 6):549-59. doi: 10.1107/S0907444911013862. Epub 2011 May 17.
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.
类固醇激素受体是哺乳动物应激和性激素系统的关键组成部分。其中许多受体依赖热休克蛋白90（Hsp90）伴侣系统来实现完整功能，并通过与Hsp90相关的肽基脯氨酰异构酶（如FK506结合蛋白51和52）进行进一步微调。FK506结合蛋白51（FKBP51）已被证明可降低糖皮质激素受体信号传导，并在基因上与人类应激恢复力以及多种精神疾病相关。FKBP51的肽基脯氨酰异构酶结构域含有一个对天然产物FK506和雷帕霉素具有高亲和力的结合位点，并且进一步证明它能传递对糖皮质激素受体的大部分抑制活性。因此，FKBP51已成为治疗与应激相关的情感障碍的主要新靶点，这类障碍可能适合基于结构的药物设计。在此，描述了FKBP51肽基脯氨酰异构酶结构域的一系列高分辨率结构以及与原型配体FK506的共晶体结构。这些结构提供了FKBP51药物结合结构域及其配体分子结合模式的详细图景，作为合理设计改进抑制剂的起点。
