Department of Chemistry, CB 3290, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, California 90095-1569, United States.
J Am Chem Soc. 2024 Oct 9;146(40):27451-27459. doi: 10.1021/jacs.4c07277. Epub 2024 Sep 25.
Histone serotonylation has emerged as a key post-translational modification. WDR5 preferentially binds to serotonylated histone 3 (H3), and this binding event has been associated with tumorigenesis. Herein, we utilize genetic code expansion, structure-activity relationship studies, and computation to study an edge-face aromatic interaction between WDR5 Phe149 and serotonin on H3 that is key to this protein-protein interaction. We find experimentally that this edge-face aromatic interaction is unaffected by modulating the electrostatics of the face component but is weakened by electron-withdrawing substituents on the edge component. Overall, these results elucidate that this interaction is governed by van der Waals forces as well as electrostatics of the edge ring, a result that clarifies discrepancies among previous theoretical models and model system studies of this interaction type. This is the first evaluation of the driving force of an edge-face aromatic interaction at a protein-protein interface and provides a key benchmark for the nature of these understudied interactions that are abundant in the proteome.
组蛋白 5 羟色胺化已成为一种关键的翻译后修饰。WDR5 优先结合 5 羟色胺化组蛋白 3（H3），这种结合事件与肿瘤发生有关。在此，我们利用遗传密码扩展、结构-活性关系研究和计算来研究 WDR5 Phe149 和 H3 上 5 羟色胺之间关键的蛋白质-蛋白质相互作用的边缘-面芳香相互作用。我们通过实验发现，这种边缘-面芳香相互作用不受调节面成分静电的影响，但受边缘成分吸电子取代基的削弱。总的来说，这些结果表明这种相互作用受范德华力和边缘环的静电作用控制，这一结果澄清了之前关于这种相互作用类型的理论模型和模型系统研究中的差异。这是对蛋白质-蛋白质界面上边缘-面芳香相互作用驱动力的首次评估，为研究这些在蛋白质组中大量存在但研究不足的相互作用的本质提供了一个关键基准。
