title: Structural Basis of Small-Molecule Aggregate Induced Inhibition of a Protein-Protein Interaction.
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.
authors.affiliation: Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , La Jolla, California 92121, United States.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Blevitt
authors.affiliation: Lead Discovery, Discovery Sciences, Janssen R&D LLC , La Jolla, California 92121, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hack
authors.affiliation: Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , La Jolla, California 92121, United States.
authors.forename: Krystal L
authors.initials: KL
authors.lastname: Herman
authors.affiliation: Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , La Jolla, California 92121, United States.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Jackson
authors.affiliation: Immunology, Janssen R&D LLC , Spring House, Pennsylvania 19477, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Krawczuk
authors.affiliation: Immunology, Janssen R&D LLC , La Jolla, California 92121, United States.
authors.forename: Alec D
authors.initials: AD
authors.lastname: Lebsack
authors.affiliation: Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , Spring House, Pennsylvania 19477, United States.
authors.forename: Annie X
authors.initials: AX
authors.lastname: Liu
authors.affiliation: Lead Discovery, Discovery Sciences, Janssen R&D LLC , La Jolla, California 92121, United States.
authors.forename: Taraneh
authors.initials: T
authors.lastname: Mirzadegan
authors.affiliation: Lead Discovery, Discovery Sciences, Janssen R&D LLC , Spring House, Pennsylvania 19477, United States.
authors.forename: Marina I
authors.initials: MI
authors.lastname: Nelen
authors.affiliation: Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , Spring House, Pennsylvania 19477, United States.
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Patrick
authors.affiliation: Proteros Biostructures , 82152 Martinsried, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Steinbacher
authors.affiliation: Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , La Jolla, California 92121, United States.
authors.forename: Marcos E
authors.initials: ME
authors.lastname: Milla
authors.affiliation: Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , Spring House, Pennsylvania 19477, United States.
authors.forename: Kevin J
authors.identifier: 0000-0003-2778-9956
authors.initials: KJ
authors.lastname: Lumb
mesh_terms: D066241:Carbon-13 Magnetic Resonance Spectroscopy; D018360:Crystallography, X-Ray; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding; D066244:Proton Magnetic Resonance Spectroscopy; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D014409:Tumor Necrosis Factor-alpha