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A conformation-selective monoclonal antibody against a small molecule-stabilised signalling-deficient form of TNF

We have recently described the development of a series of small-molecule inhibitors of human tumour necrosis factor (TNF) that stabilise an open, asymmetric, signalling-deficient form of the soluble TNF trimer. Here, we describe the generation, characterisation, and utility of a monoclonal antibody...

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Detalles Bibliográficos
Autores principales: Lightwood, Daniel J., Munro, Rebecca J., Porter, John, McMillan, David, Carrington, Bruce, Turner, Alison, Scott-Tucker, Anthony, Hickford, Elizabeth S., Schmidt, Antje, Fox, David, Maloney, Alison, Ceska, Tom, Bourne, Tim, O’Connell, James, Lawson, Alastair D. G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835358/
https://www.ncbi.nlm.nih.gov/pubmed/33495445
http://dx.doi.org/10.1038/s41467-020-20825-6
Descripción
Sumario:We have recently described the development of a series of small-molecule inhibitors of human tumour necrosis factor (TNF) that stabilise an open, asymmetric, signalling-deficient form of the soluble TNF trimer. Here, we describe the generation, characterisation, and utility of a monoclonal antibody that selectively binds with high affinity to the asymmetric TNF trimer–small molecule complex. The antibody helps to define the molecular dynamics of the apo TNF trimer, reveals the mode of action and specificity of the small molecule inhibitors, acts as a chaperone in solving the human TNF–TNFR1 complex crystal structure, and facilitates the measurement of small molecule target occupancy in complex biological samples. We believe this work defines a role for monoclonal antibodies as tools to facilitate the discovery and development of small-molecule inhibitors of protein–protein interactions.