Resolving the Structure of a Guanine Quadruplex in TMPRSS2 Messenger RNA by Circular Dichroism and Molecular Modeling

• Published in: Chemistry : a European journal 2024-12, Vol.30 (71), p.e202403572-n/a
• Main Authors: D'Anna, Luisa, Froux, Aurane, Rainot, Aurianne, Spinello, Angelo, Perricone, Ugo, Barbault, Florent, Grandemange, Stéphanie, Barone, Giampaolo, Terenzi, Alessio, Monari, Antonio
• Format: Article
• Language: English
• Subjects: Atomic structure; Cellular structure; Chemical Sciences; Circular Dichroism; Dichroism; Electronic circular dichroism; G-Quadruplexes; Guanine; Guanine - chemistry; Guanine quadruplexes; Humans; Life Sciences; Membrane fusion; Messenger RNA; Models, Molecular; Molecular dynamics; Molecular modelling; mRNA; Protein structure; Proteolysis; QM/MM Methods; RNA, Messenger - chemistry; RNA, Messenger - metabolism; SARS-CoV-2 - chemistry; SARS-CoV-2 - genetics; Secondary structure; Serine Endopeptidases - chemistry; Serine Endopeptidases - metabolism; Serine proteinase; Severe acute respiratory syndrome coronavirus 2; Viral diseases
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.202403572

The presence of a guanine quadruplex in the opening reading frame of the messenger RNA coding for the transmembrane serine protease 2 (TMPRSS2) may pave the way to original anticancer and host‐oriented antiviral strategy. Indeed, TMPRSS2 in addition to being overexpressed in different cancer types, is also related to the infection of respiratory viruses, including SARS‐CoV‐2, by promoting the cellular and viral membrane fusion through its proteolytic activity. The design of selective ligands targeting TMPRSS2 messenger RNA requires a detailed knowledge, at atomic level, of its structure. Therefore, we have used an original experimental‐computational protocol to predict the first resolved structure of the parallel guanine quadruplex secondary structure in the RNA of TMPRSS2, which shows a rigid core flanked by a flexible loop. This represents the first atomic scale structure of the guanine quadruplex structure present in TMPRSS2 messenger RNA. We have determined the structure of a guanine quadruplex motif present in the messenger RNA of the TMPRSS2 protein. By using a combination of molecular dynamics simulations and circular diuchroism spectroscopy we confirm a parallel arrangement involving a rigid tetrad core and flexible loops.