Structure of secreted aspartic proteinases from Candida. Implications for the design of antifungal agents.
Structure of secreted aspartic proteinases from Candida. Implications for the design of antifungal agents.
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念珠菌分泌的天冬氨酸蛋白酶的结构。
DOI：
10.1007/978-1-4615-5373-1_41
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发表时间：
1998
影响因子：
--
通讯作者：
Ray,TL
中科院分区：
文献类型：
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作者：
Abad-Zapatero,C;Goldman,R;Muchmore,SW;Hutchins,C;Oie,T;Stewart,K;Cutfield,SM;Cutfield,JF;Foundling,SI;Ray,TL
达氏杆菌的病原体可在免疫功能低下的患者中引起危及生命的感染。两种密切相关的分泌型天冬氨酸蛋白酶的三维结构与一种有效的（Ki=0.17 nM）抑制剂复合，以及一种类似的酶。Tropicalis揭示了经典天冬氨酸蛋白酶主题的变化，这些变化显著改变了这类酶的特异性。新的真菌蛋白酶存在：i）在第一个二硫键附近插入8个残基（Cys 45-Cys 50，胃蛋白酶编号），其导致向活性位点延伸的宽瓣; ii）替换螺旋hN 2的七个残基缺失iii）两个刚体结构域之间的短极性连接，其改变它们的相对取向并提供一定的特异性;和iv）在羧基末端的有序的12个残基加成。相同的抑制剂（A-70450）在两种白色念珠菌蛋白酶变体中以延伸构象结合，并在P3位呈现分支结构。然而，在两种晶体结构中，末端甲基哌嗪环的构象是不同的。这些研究结果的影响，为设计有效的抗真菌药物进行了讨论。
Pathogens of the genusCandidacan cause life threatening infections in immunocompromised patients. The three–dimensional structures of two closely related secreted aspartic proteinases fromC.albicanscomplexed with a potent (Ki=0.17 nM) inhibitor, and an analogous enzyme fromC. tropicalisreveal variations on the classical aspartic proteinase theme that dramatically alter the specificity of this class of enzymes. The novel fungal proteases present: i) an 8 residue insertion near the first disulfide (Cys45–Cys50, pepsin numbering) that results in a broad flap extending towards the active site; ii) a seven residue deletion replacing helix hN2(Serll0–Tyrll4), which enlarges the S3pocket; iii) a short polar connection between the two rigid body domains that alters their relative orientation and provides certain specificity; and iv) an ordered 12 residue addition at the car–boxy terminus. The same inhibitor (A–70450) binds in an extended conformation in the two variants ofC albicansprotease, and presents a branched structure at the P3 position. However, the conformation of the terminal methylpiperazine ring is different in the two crystals structures. The implications of these findings for the design of potent antifungal agents are discussed.