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Updated: Mar 6, 2026

Measuring Transcellular Interactions through Protein Aggregation in a Heterologous Cell System
Published on: May 22, 2020
Structural Basis of Small-Molecule Aggregate Induced Inhibition of a Protein-Protein Interaction
Jonathan M Blevitt1, Michael D Hack2, Krystal L Herman1
1Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , La Jolla, California 92121, United States.
Abstract:
A prevalent observation in high-throughput screening and drug discovery programs is the inhibition of protein function by small-molecule compound aggregation. Here, we present the X-ray structural description of aggregation-based inhibition of a protein-protein interaction involving tumor necrosis factor α (TNFα). An ordered conglomerate of an aggregating small-molecule inhibitor (JNJ525) induces a quaternary structure switch of TNFα that inhibits the protein-protein interaction between TNFα and TNFα receptors. SPD-304 may employ a similar mechanism of inhibition.
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