20.500.12556/RUL-156059 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. biopolymers chemical structure G-quadruplex genetics guanine biokemija g-kvadrupleksi spektroskopija NMR vnetja bolezni COVID-19 true false true Angleški jezik Slovenski jezik Članek v reviji 2024-05-06 14:41:04 2024-05-06 14:41:05 2024-05-07 03:44:59 0000-00-00 00:00:00 2024 0 0 Str. 7215–7229 iss. 6 Vol. 9 Feb. 13, 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 577 2470-1343 10.1021/acsomega.3c09592 189432835 orehova-et-al-2024-high-resolution-structure-of-rna-g-quadruplex-containing-unique-structural-motifs-originating-from.pdf orehova-et-al-2024-high-resolution-structure-of-rna-g-quadruplex-containing-unique-structural-motifs-originating-from.pdf 1 61E0CAD0652BC8FC5CF02F7CDD1638F3 c3d96e7fa899049cbd5fc0cd9c7293e414cd78fabaa5236aca62b2415d971d5c 9636fa4e-0ba6-11ef-ab55-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=183275 https://pubs.acs.org/doi/10.1021/acsomega.3c09592 0 74806a1d-0ba6-11ef-ab55-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=183274 Fakulteta za kemijo in kemijsko tehnologijo 0 0 0