Conformational Analysis of an Antibacterial Cyclodepsipeptide Active against Mycobacterium tuberculosis by a Combined ROE and RDC Analysis
Conformational Analysis of an Antibacterial Cyclodepsipeptide Active against Mycobacterium tuberculosis by a Combined ROE and RDC Analysis
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DOI：
10.1002/chem.201605143
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发表时间：
2017-04-27
影响因子：
4.3
通讯作者：
Thiele, Christina Marie
中科院分区：
文献类型：
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作者：
Fredersdorf, Maic;Kurz, Michael;Thiele, Christina Marie
Griselimycin （GM）和methylgriselimycin （MGM）是由链霉菌属微生物天然产生的由十个氨基酸组成的环状沉积肽。它们通过抑制原核DNA聚合酶ii的滑动夹钳，对分枝杆菌表现出抗菌活性，因此被认为是潜在的抗结核药物。这两种多肽的不同之处在于在氨基酸序列的第8位，MGM中存在l-(R)-4-甲基脯氨酸，而GM中存在l-脯氨酸。与GM相比，甲基化提高了MGM的代谢稳定性和活性。为了更深入地了解MGM的结构-活性关系，我们利用旋转框架核Overhauser效应（ROE）距离约束和残余偶极偶联（RDC）来确定MGM循环部分的溶液结构。将MGM在溶液中的结构与含有DNA聚合酶ii亚基β的GM在共晶中的结构进行了比较。得到了一个高度定义的MGM结构模型，该模型显示了与绑定GM相关的特征。
Griselimycin (GM) and methylgriselimycin (MGM), naturally produced by microorganisms of the genus Streptomyces, are cyclic depsipeptides composed of ten amino acids. They exhibit antibacterial activity against Mycobacterium species by inhibiting the sliding clamp of prokaryotic DNA polymeraseIII and are therefore considered as potential anti-tuberculosis drugs. The difference between the peptides is the presence of l-(R)-4-methyl-proline in MGM instead of l-proline in GM at position8 of the amino acid sequence. Methylation increases both metabolic stability and activity of MGM compared to GM. To get deeper insight into the structure-activity relationship, the solution structure of the cyclic part of MGM was determined using rotating-frame nuclear Overhauser effect (ROE) distance restraints and residual dipolar couplings (RDC). The structure of MGM in solution is compared to the structure of GM in a co-crystal with DNA polymeraseIII subunit beta. As a result, a highly defined structural model of MGM is obtained, which shows related characteristics to the bound GM.