Schlagenhauf E, Etges R, Metcalf P
EMBL Heidelberg, Biological Structures and Biocomputing Programme, Germany.
Structure. 1998 Aug 15;6(8):1035-46. doi: 10.1016/s0969-2126(98)00104-x.
Despite their medical importance, there is little available structural information for the surface antigens of infectious protozoa. Diseases caused by the protozoan parasite Leishmania are common in many developing countries. Human infection occurs during the bite of infected sandfilies, 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.
Two crystal forms of leishmanolysin were obtained from protein purified from promastigote membranes. A single lead derivative in both crystal forms 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.
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.
尽管感染性原生动物的表面抗原具有重要的医学意义，但目前关于它们的结构信息却很少。由原生动物寄生虫利什曼原虫引起的疾病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时，此时来自昆虫肠道的利什曼原虫前鞭毛体细胞进入血液。血液中的前鞭毛体寄生于巨噬细胞，常导致严重疾病。利什曼溶素是前鞭毛体的主要蛋白质表面抗原，被认为在感染过程中起关键作用。利什曼溶素是一种膜结合锌蛋白酶，在原位具有活性。类似的分子存在于其他锥虫类原生动物中。
从利什曼原虫前鞭毛体膜中纯化的蛋白质获得了两种利什曼溶素晶体形式。两种晶体形式均使用单一的铅衍生物来解析结构。该结构揭示了三个结构域，其中两个具有新颖的折叠方式。N端结构域与锌蛋白酶的催化模块具有相似的结构。该结构清楚地表明利什曼溶素是金属锌蛋白酶家族的一员。
利什曼溶素结构中意外出现的金属锌蛋白酶特征表明，金属锌蛋白酶折叠可能比现有金属锌蛋白酶之间的序列同源性所显示的更为广泛。活性位点结构与先前已充分表征的金属锌蛋白酶家族锌蛋白酶的相似性应有助于开发特异性抑制剂。这些抑制剂可用于确定利什曼溶素在昆虫和哺乳动物感染过程中的功能，并可能有助于开发治疗人类利什曼病的药物。
