ArticleBMC biology2017
A yeast two-hybrid system for the screening and characterization of small-molecule inhibitors of protein-protein interactions identifies a novel putative Mdm2-binding site in p53.
Article in BMC biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 40 citations in OpenAlex.
- Using Yeast Two-Hybrid Screening and Structural Modeling to Identify Candidate Hrr25 Kinase Interactors at the Meiotic Kinetochore inInternational journal of molecular sciences · 2026Article
- Predicting protein-protein interactions in microbes associated with cardiovascular diseases using deep denoising autoencoders and evolutionary information.Frontiers in pharmacology · 2025Article
- AlphaPPIweb: an integration platform for protein-protein interaction prediction and evaluation.American journal of cancer research · 2025Article
- ZNF500 abolishes breast cancer proliferation and sensitizes chemotherapy by stabilizing P53 via competing with MDM2.Cancer science · 2023Article
- Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction.Antioxidants (Basel, Switzerland) · 2023Article
- Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence.Journal of the American Chemical Society · 2023Review
- Neuroprotective Capability of Narcissoside in 6-OHDA-Exposed Parkinson's Disease Models through Enhancing the MiR200a/Nrf-2/GSH Axis and Mediating MAPK/Akt Associated Signaling Pathway.Antioxidants (Basel, Switzerland) · 2022Article
- Article
- A Novel Splice Variant ofCancers · 2022Article
- Protein-Protein Interaction (PPI) Network of Zebrafish Oestrogen Receptors: A Bioinformatics Workflow.Life (Basel, Switzerland) · 2022Review
- Targeting protein-protein interactions in the DNA damage response pathways for cancer chemotherapy.RSC chemical biology · 2021Review
- A Small Molecule Inhibitor of Pex3-Pex19 Interaction Disrupts Glycosome Biogenesis and Causes Lethality inFrontiers in cell and developmental biology · 2021Article
- A Potential Role for the Gsdf-eEF1α Complex in Inhibiting Germ Cell Proliferation: A Protein-Interaction Analysis in Medaka (Oryzias latipes) From a Proteomics Perspective.Molecular & cellular proteomics : MCP · 2021Article
- Molecular and Biochemical Techniques for Deciphering p53-MDM2 Regulatory Mechanisms.Biomolecules · 2020Review
- Macrocyclization of an all-d linear α-helical peptide imparts cellular permeability.Chemical science · 2020Article
- Targeting MDM2 for novel molecular therapy: Beyond oncology.Medicinal research reviews · 2020Review
- The MDM2 ligand Nutlin-3 differentially alters expression of the immune blockade receptors PD-L1 and CD276.Cellular & molecular biology letters · 2020Article
- ITRAQ-based proteomic analysis reveals possible target-related proteins in human adrenocortical adenomas.BMC genomics · 2019Article
- An Efficient Feature Extraction Technique Based on Local Coding PSSM and Multifeatures Fusion for Predicting Protein-Protein Interactions.Evolutionary bioinformatics online · 2019Article
- A patent review of the ubiquitin ligase system: 2015-2018.Expert opinion on therapeutic patents · 2018Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundProtein-protein interactions (PPIs) are fundamental to the growth and survival of cells and serve as excellent targets to develop inhibitors of biological processes such as host-pathogen interactions and cancer cell proliferation. However, isolation of PPI inhibitors is extremely challenging. While several in vitro assays to screen for PPI inhibitors are available, they are often expensive, cumbersome, and require large amounts of purified protein. In contrast, limited in vivo assays are available to screen for small-molecule inhibitors of PPI.
methodsWe have engineered a yeast strain that is suitable for screening of small-molecule inhibitors of protein-protein interaction using the Yeast 2-hybrid Assay. We have optimised and validated the assay using inhibitors of the p53-Mdm2 interaction and identified a hitherto unreported putative Mdm2-binding domain in p53.
resultsWe report a significantly improved and thoroughly validated yeast two-hybrid (Y2H) assay that can be used in a high throughput manner to screen for small-molecule PPI inhibitors. Using the p53-Mdm2 interaction to optimize the assay, we show that the p53-Mdm2 inhibitor nutlin-3 is a substrate for the yeast ATP-binding cassette (ABC) transporter Pdr5. By deleting nine ABC transporter-related genes, we generated a ABC9Δ yeast strain that is highly permeable to small molecules. In the ABC9Δ strain, p53-Mdm2 interaction inhibitors, like AMG232 and MI-773, completely inhibited the p53-Mdm2 interaction at nanomolar concentrations in the Y2H assay. In addition, we identified a conserved segment in the core DNA-binding domain of p53 that facilitates stable interaction with Mdm2 in yeast cells and in vitro.
conclusionThe Y2H assay can be utilized for high-throughput screening of small-molecule inhibitors of PPIs and to identify domains that stabilize PPIs.
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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.