7KPB

Human TNF-alpha TNFR1 complex bound to conformationally selective antibody

Summary for 7KPB

• Entry DOI: 10.2210/pdb7kpb/pdb
• Descriptor: Tumor necrosis factor, Tumor necrosis factor receptor superfamily member 1A, Fab1974 - Light Chain, ... (8 entities in total)
• Functional Keywords: tumour necrosis factor alpha, tnf, asymmetric, protein-protein inhibitor, cytokine, fragment antibody, fab, cytokine-immune system complex, cytokine/immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 7
• Total formula weight: 134088.09

Authors

Fox III, D.,Conrady, D.G.,Lowe, M.,Ceska, T. (deposition date: 2020-11-10, release date: 2021-01-13, Last modification date: 2024-10-23)

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 (3 Å)