Crystal structure of 7,8-dihydropteroate synthase from Bacillus anthracis:: Mechanism and novel inhibitor design
Crystal structure of 7,8-dihydropteroate synthase from Bacillus anthracis:: Mechanism and novel inhibitor design
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DOI：
10.1016/j.str.2004.07.011
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发表时间：
2004-09-01
期刊：
影响因子：
5.7
通讯作者：
White, SW
中科院分区：
文献类型：
--
作者：
Babaoglu, K;Qi, JJ;White, SW
二氢蝶呤合成酶(DHPS)是磺胺类抗生素的靶标，但不断增加的耐药性鼓励了针对该酶的新治疗药物的开发。一种方法是识别占据蝶呤结合口袋的分子，这与结合磺胺类药物的PABA结合口袋不同。为了实现这一目标，我们提出了来自炭疽芽孢杆菌的五种DHP晶体结构，这是一种有充分证据的生物恐怖主义制剂。已经知道三种DHPS结构，但我们的炭疽杆菌结构为酶机制提供了新的见解。我们展示了精氨酸侧链如何在蝶呤结合口袋中模拟蝶呤环的结合。两个底物模拟络合物的结构和DHPS产物络合物的第一结构为了解PABA结合口袋的催化机理和结构提供了新的见解。最后，作为蝶呤类药物开发的第一步，我们给出了与5-硝基-6-甲氨基-异胞嘧啶络合的DHPS的结构。
Dihydropterate synthase (DHPS) is the target for the sulfonamide class of antibiotics, but increasing resistance has encouraged the development of new therapeutic agents against this enzyme. One approach is to identify molecules that occupy the pterin binding pocket which is distinct from the pABA binding pocket that binds sulfonamides. Toward this goal, we present five crystal structures of DHPS from Bacillus anthracis, a well-documented bioterrorism agent. Three DHPS structures are already known, but our B. anthracis structures provide new insights into the enzyme mechanism. We show how an arginine side chain mimics the pterin ring in binding within the pterin binding pocket. The structures of two substrate analog complexes and the first structure of a DHPS-product complex offer new insights into the catalytic mechanism and the architecture of the pABA binding pocket. Finally, as an initial step in the development of pterin-based inhibitors, we present the structure of DHPS complexed with 5-nitro-6-methylamino-isocytosine.