J. Vishwakarma, V. K. Sharma, S. Kumar, R. Ramachandran
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引用次数: 0
摘要
摘要--淋巴丝虫病是一种由蚊子传播的严重寄生虫病,影响淋巴系统,导致身体部位异常肿大。它由三种相关线虫引起,其中一种是马来布鲁氏菌。胸苷酸激酶(TMK)是参与核酸代谢的主要酶。它在 Mg2+ 和 ATP 的作用下,通过催化胸腺嘧啶-5'-单磷酸(dTMP)的磷酸化形成胸腺嘧啶-5'-二磷酸(dTDP)来合成嘧啶。因此,TMK可能是开发新型抗丝虫药物的一个有吸引力的药物靶点。在此,我们报告了与 dTMP 底物结合的马拉伊氏布鲁氏菌胸苷酸激酶(BmTMK)1.91 Å 分辨率的晶体结构。该结构采用了经典的 α/β 折叠结构,就像具有核心和核苷酸结合域的 P 环 NTP 酶一样。与人类同源物的比较显示,在 TMK 结合位点和二聚体结合方面存在一些差异。小角 X 射线散射(SAXS)实验证实了 BmTMK 与人类同源物在二聚体结合方面的差异。活性位点结构的差异有可能被用来开发 BmTMK 特异性抑制剂。
Crystal Structure of the Brugia malayi Thymidylate Kinase-dTMP Complex and Small Angle X-ray Scattering Experiments Identifies Changes in the Dimeric Association Compared to the Human Homolog
Abstract—
Lymphatic filariasis is a serious parasitic disease spread by mosquitoes and affects the lymphatic system resulting in abnormal enlargement of body parts. It is caused by three related nematodes, one of which is Brugia malayi. Thymidylate kinase (TMK) is the principal enzyme involved in nucleic acid metabolism. It synthesizes pyrimidine by catalyzing the phosphorylation of thymidine-5'-monophosphate (dTMP) to form thymidine-5'-diphosphate (dTDP) in the presence of Mg2+ and ATP. Hence TMK could be an attractive drug target to develop new anti-filarials. Here, we report the crystal structure of dTMP substrate bound Brugia malayi thymidylate kinase (BmTMK) to 1.91 Å resolution. The structure adopts the classic α/β fold like P-loop NTPases with core and Nucleotide binding domains. A comparison with the human homolog shows several differences in the TMK binding site and also in the dimeric association. Small-angle X-ray scattering (SAXS) experiments support the differences in the dimeric association between BmTMK and its human counterpart. The differences in the active site architecture can possibly be exploited to develop BmTMK specific inhibitors.
期刊介绍:
Crystallography Reports is a journal that publishes original articles short communications, and reviews on various aspects of crystallography: diffraction and scattering of X-rays, electrons, and neutrons, determination of crystal structure of inorganic and organic substances, including proteins and other biological substances; UV-VIS and IR spectroscopy; growth, imperfect structure and physical properties of crystals; thin films, liquid crystals, nanomaterials, partially disordered systems, and the methods of studies.