Crystal structure of FadD32, an enzyme essential for mycolic acid biosynthesis in mycobacteria.
Crystal structure of FadD32, an enzyme essential for mycolic acid biosynthesis in mycobacteria.
复制标题
DOI：
10.1038/srep15493
复制
发表时间：
2015-12-02
影响因子：
4.6
通讯作者：
Bi L
中科院分区：
文献类型：
--
作者：
Li W;Gu S;Fleming J;Bi L
脂肪酸降解蛋白 D32 (FadD32) 是分枝菌酸生物合成所需的酶，也是分枝杆菌生长所必需的，最近已被确定为抗结核药物开发的有效且有前景的靶标。在这里，我们分别以 2.4 Å 和 2.25 Å 分辨率报道了耻垢分枝杆菌 FadD32 在 apo 和 ATP 结合状态下的晶体结构。 FadD32 由两个通过灵活接头连接的球状结构域组成。 ATP 在 N 端和 C 端结构域之间的界面处的裂缝中结合，其结合诱导 FadD32 中显着的局部构象变化。通过与腺苷酸化酶超家族的其他成员进行结构比较来鉴定分枝菌酸和磷酸泛硫氨酸的结合位点。这些结果将增进我们对 FadD32 催化机制的理解，并有助于设计这种必需酶的抑制剂。
Fatty acid degradation protein D32 (FadD32), an enzyme required for mycolic acid biosynthesis and essential for mycobacterial growth, has recently been identified as a valid and promising target for anti-tuberculosis drug development. Here we report the crystal structures of Mycobacterium smegmatis FadD32 in the apo and ATP-bound states at 2.4 Å and 2.25 Å resolution, respectively. FadD32 consists of two globular domains connected by a flexible linker. ATP binds in a cleft at the interface between the N- and C-terminal domains and its binding induces significant local conformational changes in FadD32. The binding sites of meromycolic acid and phosphopantetheine are identified by structural comparison with other members of the adenylating enzyme superfamily. These results will improve our understanding of the catalytic mechanism of FadD32 and help in the design of inhibitors of this essential enzyme.