Crystal Structures of the Free and Ligand-Bound FK1-FK2 Domain Segment of FKBP52 Reveal a Flexible Inter-Domain Hinge
Crystal Structures of the Free and Ligand-Bound FK1-FK2 Domain Segment of FKBP52 Reveal a Flexible Inter-Domain Hinge
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DOI：
10.1016/j.jmb.2013.07.041
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发表时间：
2013-11-15
影响因子：
5.6
通讯作者：
Hausch, Felix
中科院分区：
文献类型：
--
作者：
Bracher, Andreas;Kozany, Christian;Hausch, Felix
人Hsp 90共伴侣FKBP 52属于FK 506结合蛋白家族，其作为肽基-脯氨酰异构酶发挥作用。FKBP 52特异性增强类固醇激素受体的信号传导，调节离子通道并调节神经元生长动力学。反过来，FKBP 52的小分子配体已被建议作为潜在的神经营养剂或抗前列腺癌剂。然而，可用配体的有用性受到缺乏选择性的限制。亲免素FKBP 52由三个结构域组成，一个具有肽基脯氨酰异构酶活性的FK 506结合结构域，一个功能未知的FKBP样结构域和一个高亲和力识别Hsp 90 C-末端肽的TPR-钳结构域。本文报道的FKBP 52的晶体结构揭示了连接FK 506结合结构域和FKBP样结构域的短接头充当柔性铰链。这种增强的灵活性及其通过磷酸化的调节可能解释密切相关的同源物FKBP 51和FKBP 52之间的一些功能性拮抗作用。我们进一步提出了FKBP 52与原型配体FK 506及其合成类似物复合的两种共晶体结构。这些结构非常详细地揭示了分子相互作用，这使得能够与其他细胞溶质FKBP，FKBP 51和FKBP 12的相应复合物进行深入比较。观察到的细微差异为合理设计具有改善的FKBP 52选择性的配体提供了重要的见解。(C)2013爱思唯尔有限公司保留所有权利。
The human Hsp90 co-chaperone FKBP52 belongs to the family of FK506-binding proteins, which act as peptidyl-prolyl isomerases. FKBP52 specifically enhances the signaling of steroid hormone receptors, modulates ion channels and regulates neuronal outgrowth dynamics. In turn, small-molecule ligands of FKBP52 have been suggested as potential neurotrophic or anti-prostate cancer agents. The usefulness of available ligands is however limited by a lack of selectivity. The immunophilin FKBP52 is composed of three domains, an FK506-binding domain with peptidyl-prolyl isomerase activity, an FKBP-like domain of unknown function and a TPR-clamp domain, which recognizes the C-terminal peptide of Hsp90 with high affinity. The herein reported crystal structures of FKBP52 reveal that the short linker connecting the FK506-binding domain and the FKBP-like domain acts as a flexible hinge. This enhanced flexibility and its modulation by phosphorylation might explain some of the functional antagonism between the closely related homologs FKBP51 and FKBP52. We further present two co-crystal structures of FKBP52 in complex with the prototypic ligand FK506 and a synthetic analog thereof. These structures revealed the molecular interactions in great detail, which enabled in-depth comparison with the corresponding complexes of the other cytosolic FKBPs, FKBP51 and FKBP12. The observed subtle differences provide crucial insights for the rational design of ligands with improved selectivity for FKBP52. (C) 2013 Elsevier Ltd. All rights reserved.