ArticleJournal of medicinal chemistry2015
Hotspots in an obligate homodimeric anticancer target. Structural and functional effects of interfacial mutations in human thymidylate synthase.
Article in Journal of medicinal chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
15 citing papers in PubMed, 26 citations in OpenAlex.
- New insights into protein-protein interaction modulators in drug discovery and therapeutic advance.Signal transduction and targeted therapy · 2024Review
- Designing Cyclic-Constrained Peptides to Inhibit Human Phosphoglycerate Dehydrogenase.Molecules (Basel, Switzerland) · 2023Article
- Discovery of 5'-Substituted 5-Fluoro-2'-deoxyuridine Monophosphate Analogs: A Novel Class of Thymidylate Synthase Inhibitors.ACS pharmacology & translational science · 2023Article
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- SPOTONE: Hot Spots on Protein Complexes with Extremely Randomized Trees via Sequence-Only Features.International journal of molecular sciences · 2020Article
- Targeting Methyltransferases in Human Pathogenic Bacteria: Insights into Thymidylate Synthase (TS) and Flavin-Dependent TS (FDTS).Molecules (Basel, Switzerland) · 2019Review
- Structural and Functional Characterization of the Human Thymidylate Synthase (hTS) Interface Variant R175C, New Perspectives for the Development of hTS Inhibitors.Molecules (Basel, Switzerland) · 2019Article
- Evidence of Destabilization of the Human Thymidylate Synthase (hTS) Dimeric Structure Induced by the Interface Mutation Q62R.Biomolecules · 2019Article
- Structural Comparison ofMolecules (Basel, Switzerland) · 2019Article
- New Insight into the Octamer of TYMS Stabilized by Intermolecular Cys43-Disulfide.International journal of molecular sciences · 2018Article
- Noncovalent Intermediate of Thymidylate Synthase: Fact or Fiction?Journal of the American Chemical Society · 2016Article
- Intracellular quantitative detection of human thymidylate synthase engagement with an unconventional inhibitor using tetracysteine-diarsenical-probe technology.Scientific reports · 2016Article
- Substrate channeling between the human dihydrofolate reductase and thymidylate synthase.Protein science : a publication of the Protein Society · 2016Article
- Deoxyribonucleotide metabolism, mutagenesis and cancer.Nature reviews. Cancer · 2015Review
Corrections and comments
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Authors and funding
13 authors at 6 institutions in 4 countries.
Funding
Abstract
Human thymidylate synthase (hTS), a target for antiproliferative drugs, is an obligate homodimer. Single-point mutations to alanine at the monomer-monomer interface may enable the identification of specific residues that delineate sites for drugs aimed at perturbing the protein-protein interactions critical for activity. We computationally identified putative hotspot residues at the interface and designed mutants to perturb the intersubunit interaction. Dimer dissociation constants measured by a FRET-based assay range from 60 nM for wild-type hTS up to about 1 mM for single-point mutants and agree with computational predictions of the effects of these mutations. Mutations that are remote from the active site retain full or partial activity, although the substrate KM values were generally higher and the dimer was less stable. The lower dimer stability of the mutants can facilitate access to the dimer interface by small molecules and thereby aid the design of inhibitors that bind at the dimer interface.
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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.