5FUC

Biophysical and cellular characterisation of a junctional epitope antibody that locks IL-6 and gp80 together in a stable complex: implications for new therapeutic strategies

Summary for 5FUC

• Entry DOI: 10.2210/pdb5fuc/pdb
• Related: 5FUO 5FUZ
• Descriptor: INTERLEUKIN-6, INTERLEUKIN-6 RECEPTOR SUBUNIT ALPHA, INTERLEUKIN-6 RECEPTOR, VHH6, ... (5 entities in total)
• Functional Keywords: vhh, il-6, il-6 receptor alpha, il-6 receptor beta, gp80, antibody, junctional epitope, immune system
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 6
• Total formula weight: 120150.71

Authors

Adams, R.,Griffin, R.,Doyle, C.,Ettorre, A. (deposition date: 2016-01-25, release date: 2017-01-25, Last modification date: 2024-01-10)

Primary citation

Adams, R.,Burnley, R.J.,Valenzano, C.R.,Qureshi, O.,Doyle, C.,Lumb, S.,Del Carmen Lopez, M.,Griffin, R.,McMillan, D.,Taylor, R.D.,Meier, C.,Mori, P.,Griffin, L.M.,Wernery, U.,Kinne, J.,Rapecki, S.,Baker, T.S.,Lawson, A.D.,Wright, M.,Ettorre, A.
Discovery of a junctional epitope antibody that stabilizes IL-6 and gp80 protein:protein interaction and modulates its downstream signaling.
Sci Rep, 7:37716-37716, 2017

PubMed Abstract: Protein:protein interactions are fundamental in living organism homeostasis. Here we introduce VHH6, a junctional epitope antibody capable of specifically recognizing a neo-epitope when two proteins interact, albeit transiently, to form a complex. Orthogonal biophysical techniques have been used to prove the "junctional epitope" nature of VHH6, a camelid single domain antibody recognizing the IL-6-gp80 complex but not the individual components alone. X-ray crystallography, HDX-MS and SPR analysis confirmed that the CDR regions of VHH6 interact simultaneously with IL-6 and gp80, locking the two proteins together. At the cellular level, VHH6 was able to alter the response of endothelial cells to exogenous IL-6, promoting a sustained STAT3 phosphorylation signal, an accumulation of IL-6 in vesicles and an overall pro-inflammatory phenotype supported further by transcriptomic analysis. Junctional epitope antibodies, like VHH6, not only offer new opportunities in screening and structure-aided drug discovery, but could also be exploited as therapeutics to modulate complex protein:protein interactions.

PubMed: 28134246
DOI: 10.1038/srep37716

Experimental method

X-RAY DIFFRACTION (2.7 Å)