Sulfur-Oxygen Chalcogen Bonding Mediates AdoMet Recognition in the Lysine Methyltransferase SET7/9
Sulfur-Oxygen Chalcogen Bonding Mediates AdoMet Recognition in the Lysine Methyltransferase SET7/9
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DOI：
10.1021/acschembio.5b00852
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发表时间：
2016-03-01
影响因子：
4
通讯作者：
Trievel, Raymond C.
中科院分区：
文献类型：
--
作者：
Fick, Robert J.;Kroner, Grace M.;Trievel, Raymond C.
最近的研究表明碳氧（CH中心点中心点中心点O）氢键在甲基转移酶中对s -腺苷蛋氨酸（AdoMet）的识别和催化中起重要作用。在这里，我们研究了甲基转移酶活性位点的AdoMet硫阳离子和氧原子之间发生的非共价相互作用。这些相互作用代表了硫氧（S中心点中心点中心点O）的硫键，其中氧原子向AdoMet硫原子的sigma反键轨道提供了一对孤电子。结构、生化。对赖氨酸甲基转移酶SET7/9中天冬酰胺突变的计算分析表明，这种相互作用相对于产物S-腺苷型同型半胱氨酸增强了底物结合亲和力。确证的量子力学计算表明，相对于它们的中性硫醚，硫醚体系形成了强的S中心点中心点中心点O硫键。对高分辨率晶体结构的检查显示，在不同类型的甲基转移酶中存在AdoMet S中心点中心点中心点O硫键，说明这些相互作用并不局限于SET结构域甲基转移酶。总之，这些结果表明，S中心点中心点中心点O硫键有助于AdoMet识别，并使甲基转移酶能够区分底物和产物。
Recent studies have demonstrated that carbon-oxygen (CH center dot center dot center dot O) hydrogen bonds have important roles in S-adenosylmethionine (AdoMet) recognition and catalysis in methyltransferases. Here, we investigate noncovalent interactions that occur between the AdoMet sulfur cation and oxygen atoms in methyltransferase active sites. These interactions represent sulfur oxygen (S center dot center dot center dot O) chalcogen bonds in which the oxygen atom donates a lone pair of electrons to the sigma antibonding orbital of the AdoMet sulfur atom. Structural, biochemical,. and computational analyses of an asparagine mutation in the lysine methyltransferase SET7/9 that abolishes AdoMet S center dot center dot center dot O chalcogen bonding reveal that this interaction enhances substrate binding affinity relative to the product S-adenosylhomocysteine. Corroborative quantum mechanical calculations demonstrate that sulfonium systems form strong S center dot center dot center dot O chalcogen bonds relative to their neutral thioether counterparts. An inspection of high-resolution crystal structures reveals the presence of AdoMet S center dot center dot center dot O chalcogen bonding in different classes of methyltransferases, illustrating that these interactions are not limited to SET domain methyltransferases. Together, these results demonstrate that S center dot center dot center dot O chalcogen bonds contribute to AdoMet recognition and can enable methyltransferases to distinguish between substrate and product.