ArticleJournal of the American Chemical Society2020
Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products.
Article in Journal of the American Chemical Society, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 58 citations in OpenAlex.
- Monovalent Nondegrading Molecular Glues: An Updated Overview of Emerging Mechanisms and Therapeutic Development.Pharmaceuticals (Basel, Switzerland) · 2026Review
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- Cooperative Free Energy: Induced Protein-Protein Interactions and Cooperative Solvation in Ternary Complexes.Journal of chemical theory and computation · 2025Article
- Traditional Chinese medicine-based therapeutics for Pediatric pneumonia-related acute lung injury and acute respiratory distress syndrome.Scientific reports · 2025Article
- Experimental Conditions to Retrieve Intrinsic Cooperativity α Directly from Single Binding Assay Data Exemplified by the Ternary Complex Formation of FKBP12, MAPRE1 and Macrocyclic Molecular Glues.International journal of molecular sciences · 2025Article
- Total biosynthesis of cotylenin diterpene glycosides as 14-3-3 protein-protein interaction stabilizers.Chemical science · 2025Article
- Integrating protein interaction and pathway crosstalk network reveals a promising therapeutic approach for psoriasis through apoptosis induction.Scientific reports · 2024Article
- 14-3-3 Protein-Protein Interactions: From Mechanistic Understanding to Their Small-Molecule Stabilization.Chembiochem : a European journal of chemical biology · 2024Review
- Development of a NanoBRET assay for evaluation of 14-3-3σ molecular glues.SLAS discovery : advancing life sciences R & D · 2024Article
- Monotropein Protects Mesenchymal Stem Cells from Lipopolysaccharide-Induced Impairments and Promotes Fracture Healing in an Ovariectomized Mouse Model.Calcified tissue international · 2023Article
- Synthesis of (-)-Cotylenol, a 14-3-3 Molecular Glue Component.Journal of the American Chemical Society · 2023Article
- From Tethered to Freestanding Stabilizers of 14-3-3 Protein-Protein Interactions through Fragment Linking.Angewandte Chemie (International ed. in English) · 2023Article
- A model-informed method to retrieve intrinsic from apparent cooperativity and project cellular target occupancy for ternary complex-forming compounds.RSC chemical biology · 2023Article
- Protein-protein interactions: developing small-molecule inhibitors/stabilizers through covalent strategies.Trends in pharmacological sciences · 2023Review
- Fusicoccin-A Targets Cancerous Inhibitor of Protein Phosphatase 2A by Stabilizing a C-Terminal Interaction with 14-3-3.ACS chemical biology · 2022Article
- In Silico Studies on GCP-Lys-OMe as a Potential 14-3-3σ Homodimer Stabilizer.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Fragment Screening Yields a Small-Molecule Stabilizer of 14-3-3 Dimers That Modulates Client Protein Interactions.Chembiochem : a European journal of chemical biology · 2022Article
- Understanding the interaction of 14-3-3 proteins with hDMX and hDM2: a structural and biophysical study.The FEBS journal · 2022Article
- Contemporary biophysical approaches for studying 14-3-3 protein-protein interactions.Frontiers in molecular biosciences · 2022Review
- Fragment-based exploration of the 14-3-3/Amot-p130 interface.Current research in structural biology · 2022Article
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Authors and funding
10 authors at 5 institutions in 5 countries.
Funding
Abstract
Natural compounds are an important class of potent drug molecules including some retrospectively found to act as stabilizers of protein-protein interactions (PPIs). However, the design of synthetic PPI stabilizers remains an understudied approach. To date, there are limited examples where cooperativity has been utilized to guide the optimization of a PPI stabilizer. The 14-3-3 scaffold proteins provide an excellent platform to explore PPI stabilization because these proteins mediate several hundred PPIs, and a class of natural compounds, the fusicoccanes, are known to stabilize a subset of 14-3-3 protein interactions. 14-3-3 has been reported to negatively regulate the p65 subunit of the NF-κB transcription factor, which qualifies this protein complex as a potential target for drug discovery to control cell proliferation. Here, we report the high-resolution crystal structures of two 14-3-3 binding motifs of p65 in complex with 14-3-3. A semisynthetic natural product derivative, DP-005, binds to an interface pocket of the p65/14-3-3 complex and concomitantly stabilizes it. Cooperativity analyses of this interaction, and other disease relevant 14-3-3-PPIs, demonstrated selectivity of DP-005 for the p65/14-3-3 complex. The adaptation of a cooperative binding model provided a general approach to characterize stabilization and to assay for selectivity of PPI stabilizers.
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