Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden.
Department of Medical Biochemistry and Biophysics, Protein Science Facility, Karolinska Institutet, 171 77, Stockholm, Sweden.
Sci Rep. 2017 Oct 27;7(1):14288. doi: 10.1038/s41598-017-14731-z.
FK506 binding protein of 51 kDa (FKBP51) is a heat shock protein 90 (Hsp90) co-chaperone involved in the regulation of steroid hormone receptors activity. It is known for its role in various regulatory pathways implicated in mood and stress-related disorders, cancer, obesity, Alzheimer's disease and corticosteroid resistant asthma. It consists of two FKBP12 like active peptidyl prolyl isomerase (PPIase) domains (an active FK1 and inactive FK2 domain) and one tetratricopeptide repeat (TPR) domain that mediates interaction with Hsp90 via its C-terminal MEEVD peptide. Here, we report a combined x-ray crystallography and molecular dynamics study to reveal the binding mechanism of Hsp90 MEEVD peptide to the TPR domain of FKBP51. The results demonstrated that the Hsp90 C-terminal peptide binds to the TPR domain of FKBP51 with the help of di-carboxylate clamp involving Lys272, Glu273, Lys352, Asn322, and Lys329 which are conserved throughout several di-carboxylate clamp TPR proteins. Interestingly, the results from molecular dynamics study are also in agreement to the complex structure where all the contacts between these two partners were consistent throughout the simulation period. In a nutshell, our findings provide new opportunity to engage this important protein-protein interaction target by small molecules designed by structure based drug design strategy.
FK506 结合蛋白 51kDa（FKBP51）是一种热休克蛋白 90（Hsp90）共伴侣，参与调节甾体激素受体活性。它以在涉及情绪和应激相关障碍、癌症、肥胖、阿尔茨海默病和皮质类固醇耐药性哮喘的各种调节途径中的作用而闻名。它由两个 FKBP12 样活性肽基脯氨酰顺反异构酶（PPIase）结构域（活性 FK1 和非活性 FK2 结构域）和一个四肽重复（TPR）结构域组成，该结构域通过其 C 末端 MEEVD 肽与 Hsp90 介导相互作用。在这里，我们报告了一项结合 X 射线晶体学和分子动力学研究，以揭示 Hsp90 MEEVD 肽与 FKBP51 的 TPR 结构域的结合机制。结果表明，Hsp90 C 末端肽在涉及 Lys272、Glu273、Lys352、Asn322 和 Lys329 的二羧酸盐夹的帮助下与 FKBP51 的 TPR 结构域结合，这些残基在几个二羧酸盐夹 TPR 蛋白中保守。有趣的是，分子动力学研究的结果也与复合物结构一致，在整个模拟过程中，这两个伴侣之间的所有接触都保持一致。简而言之，我们的发现为通过基于结构的药物设计策略设计小分子来靶向这个重要的蛋白质-蛋白质相互作用提供了新的机会。
