ArticleScientific reports2016
Structure-Based Virtual Ligand Screening on the XRCC4/DNA Ligase IV Interface.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 20 citations in OpenAlex.
- BRCA1-A and LIG4 complexes mediate ecDNA biogenesis and cancer drug resistance.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Molecular Dynamics as a Tool for Virtual Ligand Screening.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency.The Journal of allergy and clinical immunology · 2023Article
- Microarray screening reveals two non-conventional SUMO-binding modules linked to DNA repair by non-homologous end-joining.Nucleic acids research · 2022Article
- Identification of LIG1 and LIG3 as prognostic biomarkers in breast cancer.Open medicine (Warsaw, Poland) · 2021Article
- Identification of Novel Cyclin A2 Binding Site and Nanomolar Inhibitors of Cyclin A2-CDK2 Complex.Current computer-aided drug design · 2021Article
- Druggable binding sites in the multicomponent assemblies that characterise DNA double-strand-break repair through non-homologous end joining.Essays in biochemistry · 2020Review
- DNA Ligase IV Prevents Replication Fork Stalling and Promotes Cellular Proliferation in Triple Negative Breast Cancer.Journal of nucleic acids · 2019Article
- Successful Identification of Cardiac Troponin Calcium Sensitizers Using a Combination of Virtual Screening and ROC Analysis of Known Troponin C Binders.Journal of chemical information and modeling · 2017Article
- Control of gene editing by manipulation of DNA repair mechanisms.Mammalian genome : official journal of the International Mammalian Genome Society · 2017Review
- Review
- Discovery of Anti-Hypertensive Oligopeptides from Adlay Based on In Silico Proteolysis and Virtual Screening.International journal of molecular sciences · 2016Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The association of DNA Ligase IV (Lig4) with XRCC4 is essential for repair of DNA double-strand breaks (DSBs) by Non-homologous end-joining (NHEJ) in humans. DSBs cytotoxicity is largely exploited in anticancer therapy. Thus, NHEJ is an attractive target for strategies aimed at increasing the sensitivity of tumors to clastogenic anticancer treatments. However the high affinity of the XRCC4/Lig4 interaction and the extended protein-protein interface make drug screening on this target particularly challenging. Here, we conducted a pioneering study aimed at interfering with XRCC4/Lig4 assembly. By Molecular Dynamics simulation using the crystal structure of the complex, we first delineated the Lig4 clamp domain as a limited suitable target. Then, we performed in silico screening of ~95,000 filtered molecules on this Lig4 subdomain. Hits were evaluated by Differential Scanning Fluorimetry, Saturation Transfer Difference-NMR spectroscopy and interaction assays with purified recombinant proteins. In this way we identified the first molecule able to prevent Lig4 binding to XRCC4 in vitro. This compound has a unique tripartite interaction with the Lig4 clamp domain that suggests a starting chemotype for rational design of analogous molecules with improved affinity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.