More Than π-π-π Stacking: Contribution of Amide-π and CH-π Interactions to Crotonyllysine Binding by the AF9 YEATS Domain.
More Than π-π-π Stacking: Contribution of Amide-π and CH-π Interactions to Crotonyllysine Binding by the AF9 YEATS Domain.
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DOI：
10.1021/jacs.0c06568
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发表时间：
2020-10-07
影响因子：
15
通讯作者：
Waters ML
中科院分区：
文献类型：
--
作者：
Krone MW;Travis CR;Lee GY;Eckvahl HJ;Houk KN;Waters ML
赖氨酸巴豆酰化（Kcr）是一种组蛋白翻译后修饰，与许多表观遗传途径和疾病有关。YEATS结构域对Kcr的识别被认为是通过分子间的酰胺-π和烯烃-π相互作用发生的，但对这些关键相互作用的驱动力知之甚少。在此，我们通过在两个位置掺入具有不同静电的非经典苯丙氨酸类似物，探测了AF 9 YEATS结构域对赖氨酸巴豆酰化和乙酰化的识别。我们发现AF 9和酰基赖氨酸之间的酰胺-π相互作用是静电可调的，富电子环提供更有利的相互作用。这与酰胺-杂芳烃相互作用的趋势不同，并为治疗设计提供了有见地的信息。此外，我们首次报道了Phe 28处的CH-π相互作用直接有助于AF 9对酰基赖氨酸的识别，阐明了YEATS结构域之间的差异，因为该残基不是高度保守的，但已显示出对特定翻译后修饰的选择性。
Lysine crotonylation (Kcr) is a histone post-translational modification that is implicated in numerous epigenetic pathways and diseases. Recognition of Kcr by YEATS domains has been proposed to occur through intermolecular amide–π and alkene–π interactions, but little is known about the driving force of these key interactions. Herein, we probed the recognition of lysine crotonylation and acetylation by the AF9 YEATS domain through incorporation of noncanonical Phe analogs with distinct electrostatics at two positions. We found that amide–π interactions between AF9 and acyllysines are electrostatically tunable, with electron-rich rings providing more favorable interactions. This differs from trends in amide–heteroarene interactions and provides insightful information for therapeutic design. Additionally, we report for the first time that CH–π interactions at Phe28 directly contribute to AF9’s recognition of acyllysines, illuminating differences among YEATS domains, as this residue is not highly conserved but has been shown to impart selectivity for specific post-translational modification.
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影响因子：
64.8
作者：
Erb MA;Scott TG;Li BE;Xie H;Paulk J;Seo HS;Souza A;Roberts JM;Dastjerdi S;Buckley DL;Sanjana NE;Shalem O;Nabet B;Zeid R;Offei-Addo NK;Dhe-Paganon S;Zhang F;Orkin SH;Winter GE;Bradner JE
通讯作者：
Bradner JE
影响因子：
15
作者：
Hudson KL;Bartlett GJ;Diehl RC;Agirre J;Gallagher T;Kiessling LL;Woolfson DN
通讯作者：
Woolfson DN
影响因子：
3.4
作者：
Bootsma, Andrea N.;Wheeler, Steven E.
通讯作者：
Wheeler, Steven E.
影响因子：
3.2
作者：
Cozzi, F;Annunziata, R;Siegel, JS
通讯作者：
Siegel, JS
影响因子：
5.6
作者：
Brandl, M;Weiss, MS;Hilgenfeld, R
通讯作者：
Hilgenfeld, R