High-resolution snapshots of human N-myristoyltransferase in action illuminate a mechanism promoting N-terminal Lys and Gly myristoylation
High-resolution snapshots of human N-myristoyltransferase in action illuminate a mechanism promoting N-terminal Lys and Gly myristoylation
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DOI：
10.1038/s41467-020-14847-3
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发表时间：
2020-02-28
影响因子：
16.6
通讯作者：
Giglione, Carmela
中科院分区：
文献类型：
--
作者：
Dian, Cyril;Perez-Dorado, Inmaculada;Giglione, Carmela
n -肉豆芽糖基转移酶（NMT）催化一种必需的蛋白质修饰，这种修饰被认为只发生在n端甘氨酸（Gly）上。在这里，我们展示了与活性同源脂质和肽底物共结晶的高分辨率人类NMT1结构，揭示了从初始到最终反应状态的整个催化机制的高分辨率快照。结构比较和生化分析提供了关于NMT1如何达到具有催化能力的构象的不可预见的细节，其中活性基团被靠近以实现催化。我们证明了这种机制进一步支持了n端赖氨酸侧链的高效和前所未有的肉豆蔻酰化，提供了NMT同时作为n端赖氨酸和甘氨酸肉豆蔻酰转移酶的证据。
The promising drug target N-myristoyltransferase (NMT) catalyses an essential protein modification thought to occur exclusively at N-terminal glycines (Gly). Here, we present high-resolution human NMT1 structures co-crystallised with reactive cognate lipid and peptide substrates, revealing high-resolution snapshots of the entire catalytic mechanism from the initial to final reaction states. Structural comparisons, together with biochemical analysis, provide unforeseen details about how NMT1 reaches a catalytically competent conformation in which the reactive groups are brought into close proximity to enable catalysis. We demonstrate that this mechanism further supports efficient and unprecedented myristoylation of an N-terminal lysine side chain, providing evidence that NMT acts both as N-terminal-lysine and glycine myristoyltransferase.