Koiwai Kotaro, Morohashi Kana, Inaba Kazue, Ebihara Kana, Kojima Hirotatsu, Okabe Takayoshi, Yoshino Ryunosuke, Hirokawa Takatsugu, Nampo Taiki, Fujikawa Yuuta, Inoue Hideshi, Yumoto Fumiaki, Senda Toshiya, Niwa Ryusuke
Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization, 1-1 Oho, Tsukuba, Ibaraki 305-0801, Japan.
Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
J Pestic Sci. 2021 Feb 20;46(1):75-87. doi: 10.1584/jpestics.D20-072.
Insect growth regulators (IGRs) can be developed by elucidating the molecular mechanisms of insect-specific biological events. Because insect molting, and metamorphosis are controlled by ecdysteroids, their biosynthetic pathways can serve as targets for IGR development. The glutathione -transferase Noppera-bo (Nobo), which is conserved in dipteran and lepidopteran species, plays an essential role in ecdysteroid biosynthesis. Our previous study using 17β-estradiol as a molecular probe revealed that Asp113 of Nobo (DmNobo) is essential for its biological function. However, to develop IGRs with a greater Nobo inhibitory activity than 17β-estradiol, further structural information is warranted. Here, we report five novel non-steroidal DmNobo inhibitors. Analysis of crystal structures of complexes revealed that DmNobo binds these inhibitors in an Asp113-independent manner. Among amino acid residues at the substrate-recognition site, conformation of conserved Phe39 was dynamically altered upon inhibitor binding. Therefore, these inhibitors can serve as seed compounds for IGR development.
通过阐明昆虫特异性生物学事件的分子机制，可以开发昆虫生长调节剂（IGRs）。由于昆虫的蜕皮和变态受蜕皮甾类控制，它们的生物合成途径可作为开发IGRs的靶点。谷胱甘肽 - 转移酶Noppera-bo（Nobo）在双翅目和鳞翅目物种中保守，在蜕皮甾类生物合成中起重要作用。我们之前使用17β-雌二醇作为分子探针的研究表明，Nobo（DmNobo）的Asp113对其生物学功能至关重要。然而，为了开发出比17β-雌二醇具有更强Nobo抑制活性的IGRs，还需要更多的结构信息。在此，我们报告了五种新型非甾体DmNobo抑制剂。复合物晶体结构分析表明，DmNobo以不依赖Asp113的方式结合这些抑制剂。在底物识别位点的氨基酸残基中，保守的Phe39的构象在抑制剂结合时发生动态变化。因此，这些抑制剂可作为开发IGRs的先导化合物。
