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Structure of Tetrahymena GCN5 bound to coenzyme A and a histone H3 peptide

机译：四膜虫GCN5与辅酶A和组蛋白H3肽结合的结构

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摘要

Gene activation is a highly regulated process that requires the coordinated action of proteins to relieve chromatin repression and to promote transcriptional activation. Nuclear histone acet-yltransferase (HAT) enzymes provide a mechanistic link between chromatin destabilization and gene activation by acetylating the ε-amino group of specific lysine residues within the amino-terminal tails of core histones to facilitate access to DNA by transcriptional activators. Here we report the high-resolution crystal structure of the HAT domain of Tetrahymena GCN5 (tGCN5) bound with both its physiologically relevant ligands, coenzyme A (CoA) and a histone H3 peptide, and the structures of nascent tGCN5 and a tGCN5/acetyl-CoA complex. Our structural data reveal histone-binding specificity for a random-coil structure containing a G-K-X-P recognition sequence, and show that CoA is essential for reorienting the enzyme for histone binding. Catalysis appears to involve water-mediated proton extraction from the substrate lysine by a glutamic acid general base and a backbone amide that stabilizes the transition-state reaction intermediate. Comparison with related N-acetyitransferases indicates a conserved structural framework for CoA binding and catalysis, and structural variability in regions associated with substrate-specific binding.
机译：基因激活是一个高度调控的过程，需要蛋白质的协同作用来减轻染色质阻抑并促进转录激活。核组蛋白乙酰基转移酶（HAT）酶通过乙酰化核心组蛋白氨基末端尾部特定赖氨酸残基的ε-氨基乙酰化基团来促进染色质去稳定化和基因激活之间的机制联系，以促进转录激活剂进入DNA。在这里，我们报告四膜虫GCN5（tGCN5）的HAT结构域的高分辨率晶体结构，该结构与其生理相关配体，辅酶A（CoA）和组蛋白H3肽结合，以及新生的tGCN5和tGCN5 /乙酰基-结构CoA复合体。我们的结构数据揭示了含有G-K-X-P识别序列的随机螺旋结构的组蛋白结合特异性，并表明CoA对于重新定向组蛋白结合酶至关重要。催化作用似乎涉及通过谷氨酸通用碱和稳定过渡态反应中间体的主链酰胺从底物赖氨酸中水介导的质子提取。与相关的N-乙酰基转移酶的比较表明，CoA结合和催化的结构结构保守，并且与底物特异性结合相关的区域具有结构变异性。

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