Mycobacterium tuberculosis protein tyrosine phosphatase PtpB structure reveals a diverged fold and a buried active site
Mycobacterium tuberculosis protein tyrosine phosphatase PtpB structure reveals a diverged fold and a buried active site
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DOI：
10.1016/j.str.2005.07.017
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发表时间：
2005-11-01
期刊：
影响因子：
5.7
通讯作者：
Alber, T
中科院分区：
文献类型：
--
作者：
Grundner, C;Ng, HL;Alber, T
细胞内致病菌操纵宿主信号转导通路，促进感染。结核分枝杆菌蛋白酪氨酸磷酸酶（PTPs） PtpA和PtpB被认为分泌到宿主细胞中并干扰未识别的信号。为了阐明调控和底物识别的机制，我们测定了PtpB与产物磷酸盐配合物的1.7埃分辨率晶体结构。该蛋白采用简化的PTP折叠，结合了常规PTP和双特异性磷酸酶的特点。PtpB表现出两种不同寻常的结构——一个无序的酸性环和一个覆盖活性部位的灵活的双螺旋盖——这是分枝杆菌同源物所特有的。生物化学研究表明，底物模拟的盖子可能保护磷酸酶免于氧化失活。PtpB中大结构元件的插入和删除表明，在活性位点模块之外，PTP家族处于不寻常的选择压力下，促进了整体结构的变化。
Intracellular pathogenic bacteria manipulate host signal transduction pathways to facilitate infection. Mycobacterium tuberculosis protein tyrosine phosphatases (PTPs) PtpA and PtpB are thought to be secreted into host cells and interfere with unidentified signals. To illuminate the mechanisms of regulation and substrate recognition, we determined the 1.7 angstrom resolution crystal structure of PtpB in complex with the product phosphate. The protein adopts a simplified PTP fold, which combines features of the conventional PTPs and dual-specificity phosphatases. PtpB shows two unusual elaborations-a disordered, acidic loop and a flexible, two-helix lid that covers the active site-that are specific to mycobacterial orthologs. Biochemical studies suggest that substrate mimicry in the lid may protect the phosphatase from oxidative inactivation. The insertion and deletion of large structural elements in PtpB suggest that, outside the active site module, the PTP family is under unusual selective pressure that promotes changes in overall structure.