Crystal structure of Streptococcus pneumoniae acyl carrier protein synthase:: an essential enzyme in bacterial fatty acid biosynthesis
Crystal structure of Streptococcus pneumoniae acyl carrier protein synthase:: an essential enzyme in bacterial fatty acid biosynthesis
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DOI：
10.1093/emboj/19.20.5281
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发表时间：
2000-10-16
期刊：
影响因子：
11.4
通讯作者：
Zhao, GS
中科院分区：
文献类型：
--
作者：
Chirgadze, NY;Briggs, SL;Zhao, GS
酰基载体蛋白合酶 (AcpS) 催化 Holo-ACP 的形成，在细胞内脂肪酸和脂质的生物合成过程中介导酰基脂肪酸中间体的必需转移。因此，AcpS 在细菌脂肪酸和脂质生物合成中发挥着重要作用，使其成为治疗干预的有吸引力的目标。我们首次确定了肺炎链球菌 AcpS 和与 3'5'-ADP（AcpS 的产物）复合的 AcpS 的晶体结构，分辨率分别为 2.0 和 1.9 埃。晶体结构揭示了 alp 折叠，并表明 AcpS 组装为紧密堆积的功能三聚体，具有非晶体学伪对称三重轴，其在原聚体之间的界面处包含三个活性位点。配体分子仅占据两个活性位点。尽管肺炎链球菌 AcpS 和枯草芽孢杆菌 Sfp 转移酶之间实际上不存在序列相似性，但观察到两种酶之间存在惊人的结构相似性。这些数据为基于结构的药物设计工作提供了一个起点，以鉴定具有有效抗菌活性的 AcpS 抑制剂。
Acyl carrier protein synthase (AcpS) catalyzes the formation of holo-ACP, which mediates the essential transfer of acyl fatty acid intermediates during the biosynthesis of fatty acids and lipids in the cell. Thus, AcpS plays an important role in bacterial fatty acid and lipid biosynthesis, making it an attractive target for therapeutic intervention. We have determined, for the first time, the crystal structure of the Streptococcus pneumoniae AcpS and AcpS complexed with 3'5'-ADP, a product of AcpS, at 2.0 and 1.9 Angstrom resolution, respectively. The crystal structure reveals an alp fold and shows that AcpS assembles as a tightly packed functional trimer, with a non-crystallographic pseudo-symmetric 3-fold axis, which contains three active sites at the interface between protomers. Only two active sites are occupied by the ligand molecules. Although there is virtually no sequence similarity between the S.pneumoniae AcpS and the Bacillus subtilis Sfp transferase, a striking structural similarity between both enzymes was observed. These data provide a starting point for structure-based drug design efforts towards the identification of AcpS inhibitors with potent antibacterial activity.