Hall, G, Cullen, E, Sawmynaden, K et al. (11 more authors) (2016) Structure of a potential therapeutic antibody bound to Interleukin-16 (IL-16): mechanistic insights and new therapeutic opportunities. Journal of Biological Chemistry, 291 (32). pp. 16840-16848. ISSN 0021-9258
Abstract
Interleukin-16 (IL-16) is reported to be a chemoattractant cytokine and modulator of T-cell activation, and has been proposed as a ligand for the co-receptor CD4. The secreted active form of IL-16 has been detected at sites of TH1-mediated inflammation, such as those seen in autoimmune diseases, ischemic reperfusion injury (IRI), and tissue transplant rejection. Neutralization of IL-16 recruitment to its receptor, using an anti-IL16 antibody, has been shown to significantly attenuate inflammation and disease pathology in IRI, as well as in some autoimmune diseases. The 14.1 antibody is a monoclonal anti-IL-16 antibody, which when incubated with CD4+ cells is reported to cause a reduction in the TH1-type inflammatory response. Secreted IL-16 contains a characteristic PDZ domain. PDZ domains are typically characterized by a defined globular structure, along with a peptide-binding site located in a groove between the αB and βB structural elements and a highly conserved carboxylate-binding loop. In contrast to other reported PDZ domains, the solution structure previously reported for IL-16 reveals a tryptophan residue obscuring the recognition groove. We have solved the structure of the 14.1Fab fragment in complex with IL-16, revealing that binding of the antibody requires a conformational change in the IL-16 PDZ domain. This involves the rotation of the αB-helix, accompanied movement of the peptide groove obscuring tryptophan residue, and consequent opening up of the binding site for interaction. Our study reveals a surprising mechanism of action for the antibody and identifies new opportunities for the development of IL-16-targeted therapeutics, including small molecules that mimic the interaction of the antibody.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2016, American Society for Biochemistry and Molecular Biology. This research was originally published in the Journal of Biological Chemistry as "Hall, G, Cullen, E, Sawmynaden, K, Arnold, J, Fox, S, Cowan, R, Muskett, FW, Matthews, D, Merritt, A, Kettleborough, C, Cruikshank, W, Taylor, D, Bayliss, R and Carr, MD (2016) Structure of a potential therapeutic antibody bound to IL-16: mechanistic insights and new therapeutic opportunities. Journal of Biological Chemistry, 291, 16840-16848," Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | cytokine; interleukin; monoclonal antibody; nuclear magnetic resonance (NMR); interleukin-16; protein crystallization |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 07 Jul 2016 13:18 |
Last Modified: | 20 Jul 2017 09:58 |
Published Version: | https://doi.org/10.1074/jbc.M115.709303 |
Status: | Published |
Publisher: | American Society for Biochemistry and Molecular Biology |
Identification Number: | 10.1074/jbc.M115.709303 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:102068 |