酶蛋白晶体结构 z-bio 2021-08-03 348

　　African trypanosomiasis, also known as African sleeping sickness or sleepiness encephalitis, is a zoonotic disease transmitted by trypanosomes through the bite of tsetse flies. It is endemic in sub-Saharan Africa and some endemic areas with high prevalence. At present, the development of new anti-infective drugs by blocking the endogenous sterol synthesis pathway of these trypanosomes is a hot spot in international research.

　　Recently, the research team led by the researcher Guo Ruiting of the Tianjin Institute of Industrial Biotechnology of the Chinese Academy of Sciences collaborated with the research team of Professor Eric Oldfield of UIUC University to obtain the crystal structure synthase (TcSQS) of squalene enzyme protein from trypanosoma for the first time. A total of 13 TcSQS and human-derived squalene synthase (HsSQS) composite structures were obtained, which contained substrates and inhibitors. These include substrate analogs, E5700 and ER119884 with quinuclidine structure, lipophilic diphosphates BPH1218, BPH1237, BPH1325 and BPH1344, and thiocyanate WC-9. Among them, two inhibitors including quinuclidine have high selectivity and are the direction of inhibitor development. In addition, lipophilic diphosphate inhibitors have a very effective inhibitory effect on trisomy squalene synthase, and inhibitor E5700 and azole drugs (such as posaconazole) also have an excellent synergistic effect.

　　TcSQS/HsSQS obtained the complex crystal structure of the substrate and its inhibitor. This provides a basis for understanding the catalytic mechanism of enzyme proteins and the binding sites of these inhibitors to proteins, and lays a solid foundation for the research of squalene synthase inhibitors. Provide ideas for the development of drugs for the treatment of African sleeping sickness.

　　The research results have been accepted by the top microbial journal PLOS Pathogen. Shang Na and Li Qian, assistant researchers at the Tianjin Institute of Industrial Biology, are the co-lead authors of this article.