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PDBsum entry 5fb8
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Immune system
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PDB id
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5fb8
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Contents |
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218 a.a.
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223 a.a.
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84 a.a.
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References listed in PDB file
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Key reference
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Title
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Structure of a potential therapeutic antibody bound to interleukin-16 (il-16): mechanistic insights and new therapeutic opportunities.
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Authors
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G.Hall,
E.Cullen,
K.Sawmynaden,
J.Arnold,
S.Fox,
R.Cowan,
F.W.Muskett,
D.Matthews,
A.Merritt,
C.Kettleborough,
W.Cruikshank,
D.Taylor,
R.Bayliss,
M.D.Carr.
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Ref.
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J Biol Chem, 2016,
291,
16840-16848.
[DOI no: ]
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PubMed id
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Abstract
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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.
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