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Title: Structure of a Potential Therapeutic Antibody Bound to Interleukin-16 (IL-16): Mechanistic Insights and New Therapeutic Opportunities
Authors: Hall, Gareth
Cullen, Eilish
Sawmynaden, Kovilen
Arnold, Joanne
Fox, Simon
Cowan, Richard
Muskett, Frederick W.
Matthews, David
Merritt, Andrew
Kettleborough, Catherine
Cruikshank, William
Taylor, Debra
Bayliss, Richard
Carr, Mark D.
First Published: 16-May-2016
Publisher: American Society for Biochemistry and Molecular Biology
Citation: Journal of Biological Chemistry, 2016, 291 (32), pp. 16840-16848
Abstract: Interleukin-16 (IL-16) is reported to be a chemoattractant cytokine and modulator of T-cell activation, and has been identified as a ligand for 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. Neutralisation of IL-16 recruitment to CD4, 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 characterised 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. The structure of the 14.1Fab fragment in complex with IL-16 has been solved by X-ray crystallography, revealing that binding of the antibody requires a conformational change in the IL-16 PDZ-domain. Our study reveals an unexpected mechanism of action for the mAb and identifies new opportunities for the further development of IL-16 targeted therapeutic drugs, including small molecules that mimic the interaction of the antibody.
DOI Link: 10.1074/jbc.M115.709303
ISSN: 0021-9258
eISSN: 1083-351X
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2016 American Society for Biochemistry and Molecular Biology. Deposited with reference to the publisher’s open access archiving policy.
Appears in Collections:Published Articles, Dept. of Molecular and Cell Biology

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