<br>RNA G 四链体的高分辨率结构，含有源自人酪氨酸激酶 2 (TYK2) 5'-UTR 的独特结构基序,ACS Omega

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RNA G 四链体的高分辨率结构，含有源自人酪氨酸激酶 2 (TYK2) 5'-UTR 的独特结构基序
ACS Omega ( IF 3.7 ) Pub Date : 2024-02-02 , DOI: 10.1021/acsomega.3c09592
Maria Orehova _{1,

2} , Janez Plavec _{1,

2,

3} , Vojč Kocman _{1,

2}

Affiliation

酪氨酸激酶 2 (TYK2) 是非受体相关酪氨酸激酶 JAK 家族的成员，与高度同源的 JAK1、JAK2 和 JAK3 旁系同源物一起。 TYK2 的过度表达与多种炎症性疾病相关，包括 COVID-19 感染期间的严重并发症。由于 JAK 旁系同源物的下调可能会导致严重的健康后果甚至死亡，因此在设计抑制 TYK2 的药物时避免这种情况至关重要。为了仅针对 TYK2 实现所需的特异性，研究人员最近通过开发反义寡核苷酸选择性地靶向 TYK2 mRNA。在这项工作中，我们通过证明 TYK2 mRNA 采用称为 G-四链体的四螺旋非规范结构来扩展 TYK2 mRNA 的靶空间。我们从 TYK2 mRNA 的 5'-UTR 中鉴定出TYKwt RNA 寡核苷酸，它采用平衡状态下存在的多个不同的平行 G-四链体。使用核磁共振波谱，我们发现一些 G 四链体采用独特的结构基序，这主要是由于稳定的 GA 凸起的形成。使用鸟嘌呤到尿苷的取代，我们制备了寡核苷酸TYK3_U6 ，它作为TYKwt寡核苷酸形成的凸出的 G-四链体的优秀模型。 NMR 结构分析，包括环区域残余耦合常数 (RDC) 的数据，揭示了所研究的三四重体平行 G-四链体包含许多不寻常的结构特征，例如 G(U)A 凸起、鸟嘌呤残基syn构象、堆积在顶部 G 四联体上的 A 和 U 残基，以及来自位于凹槽中的三残基长螺旋桨环的明确定义的腺嘌呤，所有这些都可能是未来药物设计的有价值的目标。

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High-Resolution Structure of RNA G-Quadruplex Containing Unique Structural Motifs Originating from the 5′-UTR of Human Tyrosine Kinase 2 (TYK2)

Tyrosine kinase 2 (TYK2) is a member of the JAK family of nonreceptor-associated tyrosine kinases together with highly homologous JAK1, JAK2, and JAK3 paralogues. Overexpression of TYK2 is associated with several inflammatory diseases, including severe complications during the COVID-19 infection. Since the downregulation of JAK paralogues could lead to serious health consequences or even death, it is critical to avoid it when designing drugs to suppress TYK2. To achieve the required specificity only for TYK2, researchers have recently selectively targeted TYK2 mRNA by developing antisense oligonucleotides. In this work, we expand the target space of TYK2 mRNA by showing that the mRNA adopts tetra-helical noncanonical structures called G-quadruplexes. We identified a TYKwt RNA oligonucleotide from the 5′-UTR of TYK2 mRNA, which adopts multiple different parallel G-quadruplexes that exist at equilibrium. Using NMR spectroscopy, we showed that some of the G-quadruplexes adopt unique structural motifs, mainly due to the formation of a stable GA bulge. Using guanine to uridine substitutions, we prepared the oligonucleotide TYK3_U6, which serves as an excellent model for the bulged G-quadruplexes formed by the TYKwt oligonucleotide. NMR structural analysis, including data on the residual coupling constants (RDC) of the loop regions, unveiled that the studied three-quartet parallel G-quadruplex contains many unusual structural features such as a G(U)A bulge, a guanine residue in the syn conformation, A and U residues stacked on the top G-quartet, and a well-defined adenine from a three-residue long propeller loop oriented in the groove, all of which could be valuable targets for future drug design.

更新日期：2024-02-02

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