Structural Basis of Small-Molecule Aggregate Induced Inhibition of a Protein Protein Interaction

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 alpha (TNF alpha). An ordered conglomerate of an aggregating small-mUlecule inhibitor (JNJ525) induces a qUaternary structure switch of TNF alpha that inhibits the protein-protein interaction between TNF alpha and TNF alpha receptors. SPD-304 may employ a similar mechanism of inhibition.