Exploring the binding nature of pyrrolidine pocket-dependent interactions in the polo-box domain of polo-like kinase 1.
Exploring the binding nature of pyrrolidine pocket-dependent interactions in the polo-box domain of polo-like kinase 1.
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DOI：
10.1371/journal.pone.0080043
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Bang JK
中科院分区：
文献类型：
--
作者：
Murugan RN;Ahn M;Lee WC;Kim HY;Song JH;Cheong C;Hwang E;Seo JH;Shin SY;Choi SH;Park JE;Bang JK
多年来，人们一直致力于设计和合成针对polo样激酶1 （Plk1）的有效线性肽抑制剂，Plk1在多个有丝分裂过程中起关键作用，并已被确定为肿瘤患者的不良预后标志物。Plk1通过其polo-box结构域定位于其细胞内的锚定位点，抑制Plk1 polo-box结构域被认为是一种规避与抑制保守的三磷酸腺苷结合口袋相关的特异性问题的方法。在三个Plk polo-box结构域（Plks 1-3）中，polo-box结构域由两个不同的结合区域组成，分别是独特的、更宽的吡咯烷结合口袋和保守的、狭窄的、富含tyrr的疏水通道。因此，深入了解独特的、更广泛的吡咯烷结合口袋的结合性质的研究可能会导致选择性plk1抑制化合物的开发。为了通过瞄准独特的、更广泛的吡咯烷结合囊来保持单特异性，在这里，首次采用系统的方法来研究n端截断的PLHSpTM衍生物的结构-活性关系，使用大型芳香和非芳香体系应用位点定向配体方法，并使用x射线晶体学研究来表征这些类似物的结合性质。我们已经确定了一种新的结合相互作用模式，在吡咯烷结合口袋中具有改进的结合亲和力和保留Plk1 polo-box结构域特异性。此外，我们的数据显示，吡咯烷结合口袋对识别短而笨重的疏水配体（如金刚烷）非常特异性，而富tyrr的疏水通道对长而小的疏水基团具有特异性。利用我们的位点定向配体取得的进展验证了这种方法，可以特异性地将配体引导到独特的吡咯烷结合区域，并扩展了发现选择性蛋白质-蛋白质相互作用抑制剂策略的适用性。
Over the years, a great deal of effort has been focused on the design and synthesis of potent, linear peptide inhibitors targeting the polo-like kinase 1 (Plk1), which is critically involved in multiple mitotic processes and has been established as an adverse prognostic marker for tumor patients. Plk1 localizes to its intracellular anchoring sites via its polo-box domain, and inhibiting the Plk1 polo-box domain has been considered as an approach to circumvent the specificity problems associated with inhibiting the conserved adenosine triphosphate-binding pocket. The polo-box domain consists of two different binding regions, such as the unique, broader pyrrolidine-binding pocket and the conserved, narrow, Tyr-rich hydrophobic channel, among the three Plk polo-box domains (Plks 1–3), respectively. Therefore, the studies that provide insights into the binding nature of the unique, broader pyrrolidine-binding pocket might lead to the development of selective Plk1-inhibitory compounds. In an attempt to retain the monospecificity by targeting the unique, broader pyrrolidine-binding pocket, here, for the first time, a systematic approach was undertaken to examine the structure-activity relationship of N-terminal-truncated PLHSpTM derivatives, to apply a site-directed ligand approach using bulky aromatic and non-aromatic systems, and to characterize the binding nature of these analogues using X-ray crystallographic studies. We have identified a new mode of binding interactions, having improved binding affinity and retaining the Plk1 polo-box domain specificity, at the pyrrolidine-binding pocket. Furthermore, our data revealed that the pyrrolidine-binding pocket was very specific to recognize a short and bulky hydrophobic ligand like adamantane, whereas the Tyr-rich hydrophobic channel was specific with lengthy and small hydrophobic groups. The progress made using our site-directed ligands validated this approach to specifically direct the ligand into the unique pyrrolidine-binding region, and it extends the applicability of the strategy for discovering selective protein-protein interaction inhibitors.
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影响因子：
4
作者：
Liu F;Park JE;Qian WJ;Lim D;Scharow A;Berg T;Yaffe MB;Lee KS;Burke TR Jr
通讯作者：
Burke TR Jr
影响因子：
56.9
作者：
DeLano, WL;Ultsch, MH;Wells, JA
通讯作者：
Wells, JA
针对 polo 样激酶 1 的 polo-box 结构域的最小磷酸肽的结构和功能分析。
影响因子：
16.8
作者：
Yun, Sang-Moon;Moulaei, Tinoush;Lim, Dan;Bang, Jeong K.;Park, Jung-Eun;Shenoy, Shilpa R.;Liu, Fa;Kang, Young H.;Liao, Chenzhong;Soung, Nak-Kyun;Lee, Sunhee;Yoon, Do-Young;Lim, Yoongho;Lee, Dong-Hee;Otaka, Akira;Appella, Ettore;McMahon, James B.;Nicklaus, Marc C.;Burke, Terrence R., Jr.;Yaffe, Michael B.;Wlodawer, Alexander;Lee, Kyung S.
通讯作者：
Lee, Kyung S.
影响因子：
16.6
作者：
Sledz, Pawel;Stubbs, Christopher J.;Lang, Steffen;Yang, Yong-Qing;McKenzie, Grahame J.;Venkitaraman, Ashok R.;Hyvoenen, Marko;Abell, Chris
通讯作者：
Abell, Chris
影响因子：
14.8
作者：
Liu, Fa;Park, Jung-Eun;Qian, Wen-Jian;Lim, Dan;Graeber, Martin;Berg, Thorsten;Yaffe, Michael B.;Lee, Kyung S.;Burke, Terrence R., Jr.
通讯作者：
Burke, Terrence R., Jr.