Substrate Engagement and Catalytic Mechanisms of N-Acetylglucosaminyltransferase V
Substrate Engagement and Catalytic Mechanisms of N-Acetylglucosaminyltransferase V
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DOI：
10.1021/acscatal.0c02222
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发表时间：
2020-08-07
期刊：
影响因子：
12.9
通讯作者：
Wu, Liang
中科院分区：
文献类型：
--
作者：
Darby, John F.;Gilio, Amelia K.;Wu, Liang
α -甘露糖苷-1,6- n -乙酰氨基葡萄糖转移酶V （MGATS）是一种哺乳动物糖基转移酶，参与复杂的TS n -聚糖形成，当过度表达时强烈驱动癌症。尽管有强烈的兴趣，但MGATS的催化机制尚不清楚，妨碍了治疗开发。我们解决了与糖基供体和受体配体络合的MGATS结构，揭示了供体诱导的环重排在控制受体底物结合方面的不可预见的作用。MGATS催化的QM/ MM元动力学模拟强调了g12297的关键辅助作用，并揭示了在转移过程中糖基供体受到的相当大的构象扭曲。MGATS的详细机制表征将有助于抑制剂的开发，以纠正癌症相关的n -糖基化。
alpha-Mannoside beta-1,6-N-acetylglucosaminyltransferase V (MGATS) is a mammalian glycosyltransferase involved in complex TS N-glycan formation, which strongly drives cancer when overexpressed. Despite intense interest, the catalytic mechanism of MGATS is not known in detail, precluding therapeutic exploitation. We solved structures of MGATS complexed to glycosyl donor and acceptor ligands, revealing an unforeseen role for donor-induced loop rearrangements in controlling acceptor substrate engagement. QM/ MM metadynamics simulations of MGATS catalysis highlight the key assisting role of G1u297 and reveal considerable conformational distortions imposed upon the glycosyl donor during transfer. Detailed mechanistic characterization of MGATS will aid inhibitor development to correct cancer-associated N-glycosylation.