The crystal structure of the Leishmania major surface proteinase leishmanolysin (gp63)
The crystal structure of the Leishmania major surface proteinase leishmanolysin (gp63)
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DOI：
10.1016/s0969-2126(98)00104-x
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发表时间：
1998-08-15
期刊：
影响因子：
5.7
通讯作者：
Metcalf, P
中科院分区：
文献类型：
--
作者：
Schlagenhauf, E;Etges, R;Metcalf, P
背景：尽管它们在医学上很重要，但感染性原生动物表面抗原的结构信息却很少。由原生动物寄生虫利什曼原虫引起的腹泻在许多发展中国家很常见，人类感染发生在被感染的白蛉叮咬期间，当利什曼原虫前鞭毛体细胞从昆虫肠道进入血液时。血液中的前鞭毛体寄生在巨噬细胞上，经常引起严重的疾病。利什曼溶血素是前鞭毛体的主要蛋白质表面抗原，并且被认为在感染期间具有关键作用。利什曼溶血素是一种膜结合锌蛋白酶，在原位有活性。结果：从前鞭毛体膜蛋白中分离得到两种晶体形式的利什曼溶血素。两个晶体农场中的单一铅衍生物用于解结构。结构揭示了三个域，其中两个具有新颖的折叠。N-末端结构域具有与锌蛋白酶的催化模块相似的结构。结构清楚地表明，利什曼溶血素是metzincin类的锌proteinases.Conclusions的成员：意想不到的metzincin功能的利什曼溶血素结构表明，metzincin倍可能是更广泛的比现有的metzincin锌蛋白酶之间的序列同源性。活性部位结构的相似性，以前很好地表征metzincin类锌蛋白酶应有助于开发特定的抑制剂，这些抑制剂可能被用来确定在昆虫和哺乳动物感染期间的利什曼溶血素的功能，并可能有助于开发人类利什曼病的药物。
Background: Despite their medical importance, there is little available structural information for the surface antigens of infectious protozoa. Diseased caused by the protozoan parasite Leishmania are common in many developing countries, Human infection occurs during the bite of infected sandflies, when Leishmania promastigote cells from the insect gut enter the bloodstream. Promastigotes in the blood parasitize macrophages, often causing serious disease. Leishmanolysin is the predominant protein surface antigen of promastigotes, and is assumed to have a key role during infection. Leishmanolysin is a membrane-bound zinc proteinase, active in situ. Similar molecules exist in other trypanomastid protozoa.Results: Two crystal forms of leishmanolysin were obtained from protein purified from promastigote membranes. A single lead derivative in both crystal farms was used to solve the structure. The structure reveals three domains, two of which have novel folds. The N-terminal domain has a similar structure to the catalytic modules of zinc proteinases. The structure clearly shows that leishmanolysin is a member of the metzincin class of zinc proteinases.Conclusions: The unexpected metzincin features of the leishmanolysin structure suggest that the metzincin fold may be more widespread than indicated by sequence homologies amongst existing metzincin zinc proteinases. The similarity of the active-site structure to previously well characterized metzincin class zinc proteinases should aid the development of specific inhibitors, These inhibitors might be used to determine the function of leishmanolysin in the insect and during mammalian infection, and may aid the development of drugs for human leishmaniasis.