7KPA

asymmetric hTNF-alpha

Summary for 7KPA

• Entry DOI: 10.2210/pdb7kpa/pdb
• Descriptor: Tumor necrosis factor, 5-(1-{[2-(difluoromethoxy)phenyl]methyl}-2-{[3-(2-oxopyrrolidin-1-yl)phenoxy]methyl}-1H-benzimidazol-6-yl)pyridin-2(1H)-one (3 entities in total)
• Functional Keywords: tnf, receptor, tnfr1, symmetric, cytokine
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 52929.77

Authors

Fox III, D.,Lukacs, C.M.,Ceska, T. (deposition date: 2020-11-10, release date: 2021-01-13, Last modification date: 2024-11-06)

Primary citation

Lightwood, D.J.,Munro, R.J.,Porter, J.,McMillan, D.,Carrington, B.,Turner, A.,Scott-Tucker, A.,Hickford, E.S.,Schmidt, A.,Fox III, D.,Maloney, A.,Ceska, T.,Bourne, T.,O'Connell, J.,Lawson, A.D.G.
A conformation-selective monoclonal antibody against a small molecule-stabilised signalling-deficient form of TNF.
Nat Commun, 12:583-583, 2021

PubMed 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.

PubMed: 33495445
DOI: 10.1038/s41467-020-20825-6

Experimental method

X-RAY DIFFRACTION (2.3 Å)