High-resolution structure of RNA G-quadruplex containing unique structural motifs originating from the 5′-UTR of human tyrosine kinase 2 (TYK2)

Orehova, Maria (avtor), Plavec, Janez (avtor), Kocman, Vojč (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: biopolymers, chemical structure, G-quadruplex, genetics, guanine
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FKKT - Fakulteta za kemijo in kemijsko tehnologijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2024
• Št. strani: Str. 7215–7229
• Številčenje: Vol. 9, iss. 6
• PID: 20.500.12556/RUL-156059
• UDK: 577
• ISSN pri članku: 2470-1343
• DOI: 10.1021/acsomega.3c09592
• COBISS.SI-ID: 189432835
• Datum objave v RUL: 06.05.2024

Gradivo je del revije

• Naslov: ACS omega
• Skrajšan naslov: ACS omega
• Založnik: American Chemical Society
• ISSN: 2470-1343
• COBISS.SI-ID: 525873945

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: biokemija, g-kvadrupleksi, spektroskopija, NMR, vnetja, bolezni, COVID-19

Projekti

• Financer: ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
• Številka projekta: P1-0242
• Naslov: Kemija in struktura bioloških učinkovin

• Financer: ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
• Številka projekta: Z1-3192
• Naslov: Strukturna in dinamična karakterizacija mitohondrijskih transportnih RNA (mt-tRNA) in njihovih fragmentov