5FB8

Structure of Interleukin-16 bound to the 14.1 antibody

Summary for 5FB8

• Entry DOI: 10.2210/pdb5fb8/pdb
• Related: 1I16
• Descriptor: Anti-IL-16 antibody 14.1 Fab domain Kappa Chain, Anti-IL-16 antibody 14.1 Fab domain Heavy Chain, Pro-interleukin-16, ... (7 entities in total)
• Functional Keywords: cytokine, interleukin, antibody, complex, immune system
• Biological source: Mus musculus (House Mouse); More
• Cellular location: Interleukin-16: Secreted. Isoform 1: Cytoplasm . Isoform 3: Cytoplasm: Q14005
• Total number of polymer chains: 3
• Total formula weight: 59630.57

Authors

Hall, G.,Cowan, R.,Bayliss, R.,Carr, M. (deposition date: 2015-12-14, release date: 2016-06-08, Last modification date: 2024-11-20)

Primary citation

Hall, G.,Cullen, E.,Sawmynaden, K.,Arnold, J.,Fox, S.,Cowan, R.,Muskett, F.W.,Matthews, D.,Merritt, A.,Kettleborough, C.,Cruikshank, W.,Taylor, D.,Bayliss, R.,Carr, M.D.
Structure of a Potential Therapeutic Antibody Bound to Interleukin-16 (IL-16): MECHANISTIC INSIGHTS AND NEW THERAPEUTIC OPPORTUNITIES.
J.Biol.Chem., 291:16840-16848, 2016

PubMed 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.

PubMed: 27231345
DOI: 10.1074/jbc.M115.709303

Experimental method

X-RAY DIFFRACTION (2.07 Å)