Structures of the eIF4G-binding RNA domains among picornaviral IRES types are topologically conserved
Year: 2026
Type: article
Abstract: RNA domains within viral IRESs are crucial for initiating cap-independent translation of the genome in many positive-sense RNA viruses. However, the structures and mechanisms of these IRES domains remain unclear. Here, we present the 3 Å resolution crystal structure of the coxsackievirus B3 (CVB3) IRES domain V (dV) as a model for type I IRESs. The crystal structure revealed an elongated architecture of dV, with two sets of coaxially stacked stems forming an H-type four-way junction (4WJ) organized by an A-rich motif. Despite sequence dissimilarities, this dV from a type I IRES exhibits remarkable structural similarity to the analogous tertiary structures of the encephalomyocarditis virus (EMCV) JK domain and the hepatitis A virus (HAV) dV, which are typical domains in the type II and III IRESs, respectively. While SAXS studies indicate a similar RNA fold of dV in solution, structure-guided binding, computational modeling, and X-ray footprinting studies with and without the HEAT1 domain of eIF4G, compared to the analogous type II (EMCV JK) and III (HAV dV) domains, suggest that various IRESs maintain a common mechanism of eIF4G binding interactions during viral genome translation. Despite sequence variability, this structural conservation across IRES types may offer unique opportunities to develop universal antivirals targeting these structures.
Source: Nature Communications
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Science Foundation, U.S. Department of Energy, Johns Hopkins University, Case Western Reserve University, National Institutes of Health, Office of Science, National Institute of General Medical Sciences, Basic Energy Sciences, Biological and Environmental Research, Argonne National Laboratory, Brookhaven National Laboratory, Lawrence Berkeley National Laboratory
Awards: G1063373159, G1285306620, G171842289, G1847291448, G1867732070, G2013908898, MRI Consortium: Development of a Damping Wiggler Beamline for X-Ray Footprinting at NSLS II, G241279073, G2776070826, G3262563802, G3388457521, G357145406, G4523881014, G5765906131, G6047080114, G6206027980, G6476969910, G6816383395, G6965541988, G6985549539, G7463374569, G7799234019, G8229677252, G8461821187, G872144517, G8775485830, G9000263589, Center for Biomolecular Structure (CBMS), Assembly Mechanisms of RNA-Protein Complexes for Genetic Control, ALS Efficiently Networking Advanced Beam Line Experiments (ALS-ENABLE), Graduate Training at The Chemistry Biology Interface, Structural and mechanistic studies of cap-independent genome translation in (+)-strand RNA viruses
OpenAlex ID: W7128926730