Structure of a secreted aspartic protease from C. albicans complexed with a potent inhibitor: implications for the design of antifungal agents.
Structure of a secreted aspartic protease from C. albicans complexed with a potent inhibitor: implications for the design of antifungal agents.
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白色念珠菌分泌的天冬氨酸蛋白酶与有效抑制剂复合的结构：对抗真菌药物设计的影响。
DOI：
10.1002/pro.5560050408
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Ray,TL
中科院分区：
文献类型：
--
作者：
Abad-Zapatero,C;Goldman,R;Muchmore,SW;Hutchins,C;Stewart,K;Navaza,J;Payne,CD;Ray,TL
白色念珠菌分泌的天冬氨酸蛋白酶与一种强效抑制剂的三维结构揭示了经典天冬氨酸蛋白酶主题的变化，这种变化极大地改变了这类酶的特异性。该结构表现为：(1)在第一个二硫化物（Cys 45 - Cys 50，胃蛋白酶编号）附近有一个8‐残基插入，导致一个向活性位点延伸的宽瓣；(2) 7个残基的缺失取代了螺旋hN2(Ser 110‐Tyr 114)，扩大了S3pocket；(3)两个刚体域之间的短极性连接改变了它们的相对方向并提供了一定的特异性；(4)在羧基端有一个有序的11‐残基加成。抑制剂以扩展构象结合，并在P3位置呈现支链结构。讨论了这些发现对设计有效抗真菌药物的意义。
The three‐dimensional structure of a secreted aspartic protease fromCandida albicanscomplexed with a potent inhibitor reveals variations on the classical aspartic protease theme that dramatically alter the specificity of this class of enzymes. The structure presents: (1) an 8‐residue insertion near the first disulfide (Cys 45‐Cys 50, pepsin numbering) that results in a broad flap extending toward the active site; (2) a 7‐residue deletion replacing helix hN2(Ser 110‐Tyr 114), which enlarges the S3pocket; (3) a short polar connection between the two rigid body domains that alters their relative orientation and provides certain specificity; and (4) an ordered 11‐residue addition at the carboxy terminus. The inhibitor binds in an extended conformation and presents a branched structure at the P3 position. The implications of these findings for the design of potent antifungal agents are discussed.