Biology subjects

Jo, G.

Publications and source records attributed to Jo, G..

3 recordsLinked to original sources

bioRxiv2025

APE1 Coordinates Its Disordered Region and Metal Cofactors to Drive Genome Surveillance

Efficient recognition of DNA lesions such as apurinic/apyrimidinic (AP) sites is essential for maintaining genome stability. Apurinic/apyrimidinic endonuclease 1 (APE1) is the primary eukaryotic AP endonuclease, yet how it identifies rare lesions among vast stretches of undamaged DNA remains incompletely understood. Using single-molecule imaging combined with molecular dynamics simulations, we reveal that APE1 employs a distinctive dual mechanism to search DNA. First, Mg{superscript 2} coordination at the active site neutralizes clustered negative charges, stabilizing electrostatic contacts during scanning. Second, its N-terminal intrinsically disordered region (IDR)--a feature conserved only in eukaryotic homologs but absent in prokaryotic ExoIII--not only forms DNA through transient IDR contacts but also engages continuous interactions via the unprecedented 177 arginine residue within the structured nuclease domain, thereby prolonging residence time and enabling long-range diffusion. Together, these two modules synergize to promote a sliding-based search strategy tailored to the complexity of eukaryotic genomes. Consistent with this model, IDR deletion restricts APE1 to 3D collisions, whereas IDR duplication enhances 1D scanning. Thus, APE1 exemplifies how structural disorder and metal-ion coordination integrate to enable long-range lesion recognition, highlighting an evolutionary innovation in eukaryotic DNA repair.

molecular biology↗

bioRxiv2025

Antiviral and anti-inflammatory effects of Tabamide A derivative, TA25, against human rhinovirus and multiple zoonotic viruses in vitro and in silico

Human rhinovirus (HRV), first isolated in 1956, belongs to the family Piconaviridae containing a positive-sense, single-stranded RNA genome. HRV causes mild cold and severe respiratory disease, such as asthma, COPD, and pneumonia. To date, no Food and Drug Administration-approved antiviral or anti-inflammatory drugs are available for HRV. TA25 is a phenolic amide derivative extracted from the leaves of Nicotiana tabacum. To investigate the potential candidate for antiviral therapeutics against zoonotic viruses, we evaluated the antiviral potency of TA25 for HRV and multiple zoonotic viruses. The antiviral and anti-inflammatory effects of TA25 were evaluated using RT-qPCR and RNA-seq. Strand-specific RT-qPCR was performed to measure genomic and anti-genomic RNA expression after TA25 treatment. In addition, an AI-based docking test was conducted to investigate the binding affinity of TA25 with viral target proteins. TA25 induced a significant reduction in viral replication and suppressed the expression of pro-inflammatory genes. Inhibition of viral replication by TA25 treatment was confirmed by strand-specific RT-qPCR. TA25 showed broad-spectrum antiviral activity against multiple viruses, including HRV-1A, Zika virus, Dengue virus, Vaccinia virus, and Influenza B virus Victoria. Using an AI-driven structure-based docking analysis, TA25 showed the strongest binding affinity with the HRV 2B protein. This study demonstrates that TA25 confers the broad antiviral and anti-inflammatory activity against HRV and multiple zoonotic viruses. These findings provide valuable insights into antiviral strategies of TA25 for a promising therapeutic candidate in response to emerging RNA and DNA viruses.

microbiology↗

bioRxiv2024

Structural basis of broad protection against influenza virus by a human antibody targeting the neuraminidase active site via a recurring motif in CDR H3

Influenza viruses evolve rapidly, driving seasonal epidemics and posing global pandemic threats. While neuraminidase (NA) has emerged as a vaccine target, shared molecular features of NA antibody responses are still not well understood. Here, we describe cryo-electron microscopy structures of the broadly protective human antibody DA03E17, which was previously identified from an H1N1-infected donor, in complex with NA from A/H1N1, A/H3N2, and B/Victoria-lineage viruses. DA03E17 targets the highly conserved NA active site using its long CDR H3, which features a DR (Asp-Arg) motif that engages catalytic residues and mimics sialic acid interactions. We further demonstrate that this motif is conserved among several NA active site-targeting antibodies, indicating a common receptor mimicry strategy. We also identified potential antibody precursors containing this DR motif in all donors of a healthy human donor BCR database, highlighting the prevalence of this motif and its potential as vaccine targeting. Our findings reveal shared molecular features in NA active site-targeting antibodies, offering insights for NA-based universal influenza vaccine design.

immunology↗