Structural Basis of Small-Molecule Aggregate Induced Inhibition of a Protein-Protein Interaction - PubMed (original) (raw)

. 2017 Apr 27;60(8):3511-3517.

doi: 10.1021/acs.jmedchem.6b01836. Epub 2017 Mar 16.

Michael D Hack 2, Krystal L Herman 1, Paul F Jackson 1, Paul J Krawczuk 3, Alec D Lebsack 4, Annie X Liu 5, Taraneh Mirzadegan 2, Marina I Nelen 6, Aaron N Patrick 5, Stefan Steinbacher 7, Marcos E Milla 1, Kevin J Lumb 5

Affiliations

• PMID: 28300404
• DOI: 10.1021/acs.jmedchem.6b01836

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

Jonathan M Blevitt et al. J Med Chem. 2017.

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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