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首页> 外文期刊>Journal of Molecular Biology >Crystal structures of mouse autocrine motility factor in complex with carbohydrate phosphate inhibitors provide insight into structure-activity relationship of the inhibitors.
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Crystal structures of mouse autocrine motility factor in complex with carbohydrate phosphate inhibitors provide insight into structure-activity relationship of the inhibitors.

机译：小鼠自分泌运动因子与碳水化合物磷酸盐抑制剂复合的晶体结构提供了对抑制剂的构效关系的了解。

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Autocrine motility factor (AMF), a tumor-secreted cytokine, stimulates cell migration in vitro and metastasis in vivo. AMF is identical to the extracellular cytokines neuroleukin and maturation factor and, interestingly, to the intracellular enzyme phosphoglucose isomerase. The cytokine activity of AMF is inhibited by carbohydrate phosphate compounds as they compete for AMF binding with the carbohydrate moiety of the AMF receptor (AMFR), which is a glycosylated seven transmembrane helix protein. Here, we report the first comprehensive high-resolution crystal structure analyses of the inhibitor-free form and the eight types of inhibitor (phosphate, erythrose 4-phosphate (E4P), arabinose 5-phosphate (A5P), sorbitol 6-phosphate (S6P), 6-phosphogluconic acid (6PGA), fructose 6-phosphate (F6P), glucose 6-phosphate (G6P), or mannose 6-phosphate (M6P)) complexes of mouse AMF (mAMF). We assayed the inhibitory activities of these inhibitors against the cytokine activity of mAMF. The inhibitory activities of thesix-carbon sugars (G6P, F6P, M6P, and 6PGA) were found to be significantly higher than those of the four or five-carbon sugars (E4P or A5P). The inhibitory activities clearly depend on the length of the inhibitor molecules. A structural comparison revealed that a water-mediated hydrogen bond between one end of the inhibitor and a rigid portion of the protein surface in the shorter-chain inhibitor (E4P) complex is replaced by a direct hydrogen bond in the longer-chain inhibitor (6PGA) complex. Thus, to obtain a new compound with higher inhibitory activities against AMF, water molecules at the inhibitor binding site of AMF should be replaced by a functional group of inhibitors in order to introduce direct interactions with the protein surface. The present structure-activity relationship studies will be valuable not only for designing more effective AMF inhibitors but also for studying general protein-inhibitor interactions.
机译：自分泌运动因子（AMF）是一种肿瘤分泌的细胞因子，可在体外刺激细胞迁移并在体内转移。 AMF与细胞外细胞因子神经白蛋白和成熟因子相同，而与细胞内酶磷酸葡萄糖异构酶相同。碳水化合物磷酸酯化合物会抑制AMF的细胞因子活性，因为它们竞争AMF与AMF受体（AMFR）的碳水化合物部分（一种糖基化的7个跨膜螺旋蛋白）结合。在这里，我们报告了无抑制剂形式和八种抑制剂（磷酸盐，赤藓糖4磷酸酯（E4P），阿拉伯糖5磷酸酯（A5P），山梨糖醇6磷酸酯（S6P）的第一个全面的高分辨率晶体结构分析），小鼠AMF（mAMF）的6-磷酸葡萄糖酸（6PGA），果糖6-磷酸（F6P），葡萄糖6-磷酸（G6P）或甘露糖6-磷酸（M6P））复合物。我们测定了这些抑制剂对mAMF的细胞因子活性的抑制活性。发现六碳糖（G6P，F6P，M6P和6PGA）的抑制活性明显高于四或五碳糖（E4P或A5P）。抑制活性显然取决于抑制剂分子的长度。结构比较表明，抑制剂的一端与较短链抑制剂（E4P）复合物中蛋白质表面的刚性部分之间的水介导氢键被较长链抑制剂（6PGA）中的直接氢键取代）复杂。因此，为了获得对AMF具有更高抑制活性的新化合物，AMF的抑制剂结合位点处的水分子应被抑制剂的官能团取代，以引入与蛋白质表面的直接相互作用。当前的结构-活性关系研究不仅对于设计更有效的AMF抑制剂，而且对于研究一般的蛋白质-抑制剂相互作用都是有价值的。

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