ArticleNucleic acids research2016
Structures of mithramycin analogues bound to DNA and implications for targeting transcription factor FLI1.
Article in Nucleic acids research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 34 citations in OpenAlex.
- Crystal Structure of Trabectedin-DNA Complex.Journal of molecular biology · 2026Article
- The structures of ecteinascidin anticancer agents bound to DNA shed light on their mechanism of action.Nucleic acids research · 2026Article
- Natural Products Beyond Inhibition: A Mechanistic Framework Spanning Pockets, Interfaces, and Kinetic Barriers.Molecules (Basel, Switzerland) · 2026Review
- Mithramycin alters EWS::FLI1 DNA binding and RNA polymerase II processivity to inhibit nascent transcription.Nature communications · 2026Article
- The Position of Indole Methylation Controls the Structure, DNA Binding, and Cellular Functions of Mithramycin SA-Trp Analogues.Chembiochem : a European journal of chemical biology · 2025Article
- Structure and cooperative formation of a FLI1 filament on contiguous GGAA DNA sites.Nucleic acids research · 2025Article
- Mithplatins: Mithramycin SA-Pt(II) Complex Conjugates for the Treatment of Platinum-Resistant Ovarian Cancers.ChemMedChem · 2023Article
- "Stripe" transcription factors provide accessibility to co-binding partners in mammalian genomes.Molecular cell · 2022Article
- Interleukin-10 suppression enhances T-cell antitumor immunity and responses to checkpoint blockade in chronic lymphocytic leukemia.Leukemia · 2021Article
- Allosteric interference in oncogenic FLI1 and ERG transactions by mithramycins.Structure (London, England : 1993) · 2021Article
- Review
- Mithramycin 2'-Oximes with Improved Selectivity, Pharmacokinetics, and Ewing Sarcoma Antitumor Efficacy.Journal of medicinal chemistry · 2020Article
- Article
- Discovery of a Cryptic Intermediate in Late Steps of Mithramycin Biosynthesis.Angewandte Chemie (International ed. in English) · 2020Article
- Article
- Identification of diterpenoid compounds that interfere with Fli-1 DNA binding to suppress leukemogenesis.Cell death & disease · 2019Article
- Chromomycin AThe Journal of general physiology · 2018Article
- Development of Mithramycin Analogues with Increased Selectivity toward ETS Transcription Factor Expressing Cancers.Journal of medicinal chemistry · 2018Article
- A survey of recent unusual high-resolution DNA structures provoked by mismatches, repeats and ligand binding.Nucleic acids research · 2018Review
- Targeting Transcription Factors for Cancer Treatment.Molecules (Basel, Switzerland) · 2018Review
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Transcription factors have been considered undruggable, but this paradigm has been recently challenged. DNA binding natural product mithramycin (MTM) is a potent antagonist of oncogenic transcription factor EWS-FLI1. Structural details of MTM recognition of DNA, including the FLI1 binding sequence GGA(A/T), are needed to understand how MTM interferes with EWS-FLI1. We report a crystal structure of an MTM analogue MTM SA-Trp bound to a DNA oligomer containing a site GGCC, and two structures of a novel analogue MTM SA-Phe in complex with DNA. MTM SA-Phe is bound to sites AGGG and GGGT on one DNA, and to AGGG and GGGA(T) (a FLI1 binding site) on the other, revealing how MTM recognizes different DNA sequences. Unexpectedly, at sub-micromolar concentrations MTMs stabilize FLI1-DNA complex on GGAA repeats, which are critical for the oncogenic function of EWS-FLI1. We also directly demonstrate by nuclear magnetic resonance formation of a ternary FLI1-DNA-MTM complex on a single GGAA FLI1/MTM binding site. These biochemical and structural data and a new FLI1-DNA structure suggest that MTM binds the minor groove and perturbs FLI1 bound nearby in the major groove. This ternary complex model may lead to development of novel MTM analogues that selectively target EWS-FLI1 or other oncogenic transcription factors, as anti-cancer therapeutics.
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Registered trials
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.