A conformation-selective monoclonal antibody against a small molecule-stabilised signalling-deficient form of TNF
| Autor: | Alison Maloney, John Robert Porter, O'connell James Philip, Bruce Carrington, Alison Turner, David A. Fox, Tom Ceska, David McMillan, Anthony Scott-Tucker, Antje Schmidt, Daniel John Lightwood, Tim Bourne, Rebecca Munro, Alastair D. G. Lawson, Elizabeth S. Hickford |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular 0301 basic medicine Protein Conformation medicine.drug_class Science General Physics and Astronomy Trimer Mechanism of action Crystallography X-Ray Monoclonal antibody Article General Biochemistry Genetics and Molecular Biology Small Molecule Libraries Epitopes 03 medical and health sciences 0302 clinical medicine Antibody generation medicine Humans Receptor Cells Cultured X-ray crystallography Multidisciplinary biology Tumor Necrosis Factor-alpha Chemistry HEK 293 cells Tumour-necrosis factors Antibodies Monoclonal General Chemistry Small molecule Cell biology HEK293 Cells 030104 developmental biology Receptors Tumor Necrosis Factor Type I Multiprotein Complexes Chaperone (protein) biology.protein Tumor necrosis factor alpha Antibody 030217 neurology & neurosurgery Protein Binding Signal Transduction |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-10 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|