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- Title
A conformation-selective monoclonal antibody against a small molecule-stabilised signalling-deficient form of TNF.
- Authors
Lightwood, Daniel J.; Munro, Rebecca J.; Porter, John; McMillan, David; Carrington, Bruce; Turner, Alison; Scott-Tucker, Anthony; Hickford, Elizabeth S.; Schmidt, Antje; Fox III, David; Maloney, Alison; Ceska, Tom; Bourne, Tim; O'Connell, James; Lawson, Alastair D. G.
- Abstract
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. TNF can be inhibited by small molecules that stabilize the TNF trimer in an asymmetric conformation. Here, the authors develop a monoclonal antibody that selectively binds this inactive form of TNF, enabling both target engagement assessment and structural characterization of TNF binding to TNF receptor 1.
- Subjects
SMALL molecules; MOLECULAR dynamics; TUMOR necrosis factor receptors; PROTEIN-protein interactions; MONOCLONAL antibodies; CRYSTAL structure; MOLECULAR chaperones
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-20825-6