PloS one, 2017-06, Vol.12 (6), p.e0178381-e0178381
2017
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Details
- Autor(en) / Beteiligte
- Titel
- Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches
- Ist Teil von
- PloS one, 2017-06, Vol.12 (6), p.e0178381-e0178381
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2017
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- The Hippo signaling pathway, which is implicated in the regulation of organ size, has emerged as a potential target for the development of cancer therapeutics. YAP, TAZ (transcription co-activators) and TEAD (transcription factor) are the downstream transcriptional machinery and effectors of the pathway. Formation of the YAP/TAZ-TEAD complex leads to transcription of growth-promoting genes. Conversely, disrupting the interactions of the complex decreases cell proliferation. Herein, we screened a 1000-member fragment library using Thermal Shift Assay and identified a hit fragment. We confirmed its binding at the YAP/TAZ-TEAD interface by X-ray crystallography, and showed that it occupies the same hydrophobic pocket as a conserved phenylalanine of YAP/TAZ. This hit fragment serves as a scaffold for the development of compounds that have the potential to disrupt YAP/TAZ-TEAD interactions. Structure-activity relationship studies and computational modeling were also carried out to identify more potent compounds that may bind at this validated druggable binding site.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0178381Titel-ID: cdi_plos_journals_1904975976
- Format
- –
- Schlagworte
- Animals, Assaying, Binding, Bioinformatics, Biology, Biology and Life Sciences, Calorimetry, Cancer, Cell growth, Cell proliferation, Chemistry, Computer applications, Computer Simulation, Control, Crystallography, Crystallography, X-Ray, Disruption, Drug development, Effectors, Fragmentation, Gene expression, Genes, Genetic aspects, Humans, Hydrophobicity, Ligands, Machinery and equipment, Mathematical models, Medical screening, Mice, Peptides, Phenylalanine, Physical Sciences, Protein Binding, Protein interaction, Protein-protein interactions, Proteins, Research and Analysis Methods, Science, Signal transduction, Structure-Activity Relationship, Transcription (Genetics), Transcription factors, Transcription Factors - chemistry, Transcription Factors - metabolism, Tumorigenesis, X-ray crystallography, Yes-associated protein