...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Acta crystallographica. Section D, Structural biology >Structural insights into the antifungal drug target guanosine monophosphate synthase from Aspergillus fumigatus
【24h】

Structural insights into the antifungal drug target guanosine monophosphate synthase from Aspergillus fumigatus

机译：结构洞察抗真菌药物目标鸟苷酸合成酶来自烟曲霉属真菌

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Purine biosynthesis is a fundamental cellular process that sustains life by maintaining the intracellular pool of purines for DNA/RNA synthesis and signal transduction. As an integral determinant of fungal survival and virulence, the enzymes in this metabolic pathway have been pursued as potential antifungal targets. Guanosine monophosphate (GMP) synthase has been identified as an attractive target as it is essential for virulence in the clinically prominent fungal pathogens Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans. However, a lack of structural information on GMP synthase has hindered drug-design efforts. Here, the first structure of a GMP synthase of fungal origin, that from A. fumigatus (at 2.3 angstrom resolution), is presented. Structural analysis of GMP synthase shows a distinct absence of the D1 dimerization domain that is present in the human homologue. Interestingly, A. fumigatus GMP synthase adopts a dimeric state, as determined by native mass spectrometry and gel-filtration chromatography, in contrast to the monomeric human homologue. Analysis of the substrate-binding pockets of A. fumigatus GMP synthase reveals key differences in the ATP- and XMP-binding sites that can be exploited for species-specific inhibitor drug design. Furthermore, the inhibitory activities of the glutamine analogues acivicin (IC50 = 16.6 +/- 2.4 mu M) and 6-diazo-5-oxo-L-norleucine (IC50 = 29.6 +/- 5.6 mu M) against A. fumigatus GMP synthase are demonstrated. Together, these data provide crucial structural information required for specifically targeting A. fumigatus GMP synthase for future antifungal drug-discovery endeavours.
机译：嘌呤生物合成是一个基本的细胞维护过程,维持生活细胞内的嘌呤DNA / RNA合成和信号转导。真菌生存和毒性的行列式酶在代谢途径追求作为潜在的抗真菌的目标。鸟苷酸合成酶(GMP)确定为一个有吸引力的目标重要的临床毒性的著名的真菌病原体来自烟曲霉菌,白色念珠菌、新型隐球菌。然而,缺乏对GMP的结构信息合酶阻碍了药物设计工作。第一个结构GMP合酶的真菌起源,从来自烟(2.3埃分辨率)。GMP合酶显示了D1明显缺乏二聚作用域存在于人类同系物。合酶采用二聚的状态,决定了质谱法和凝胶过滤色谱法,与单体的人类的同系物。来自烟substrate-binding口袋的GMPATP合酶显示关键的差异,XMP-binding网站可以利用种专一性抑制剂药物设计。此外,抑制活动谷氨酰胺类似acivicin (IC50 = 16.6 + / - 2.4μM)和6-diazo-5-oxo-L-norleucine (IC50 = 29.6+ / - 5.6μM)对来自烟GMP合成酶演示了。关键结构所需的信息专门针对来自烟GMP合成酶努力为未来抗真菌药物。

著录项

相似文献

  • 外文文献
  • 中文文献
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号