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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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PDB id:
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Immune system
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Title:
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Structure of interleukin-16 bound to the 14.1 antibody
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Structure:
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Anti-il-16 antibody 14.1 fab domain kappa chain. Chain: a. Engineered: yes. Anti-il-16 antibody 14.1 fab domain heavy chain. Chain: b. Engineered: yes. Pro-interleukin-16. Chain: c. Fragment: unp residues 1224-1323.
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Source:
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Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: expi293f. Homo sapiens. Human. Organism_taxid: 9606.
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Resolution:
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2.07Å
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R-factor:
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0.174
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R-free:
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0.205
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Authors:
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G.Hall,R.Cowan,R.Bayliss,M.Carr
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Key ref:
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G.Hall
et al.
(2016).
Structure of a Potential Therapeutic Antibody Bound to Interleukin-16 (IL-16): MECHANISTIC INSIGHTS AND NEW THERAPEUTIC OPPORTUNITIES.
J Biol Chem,
291,
16840-16848.
PubMed id:
DOI:
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Date:
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14-Dec-15
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Release date:
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08-Jun-16
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PROCHECK
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Headers
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References
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No UniProt id for this chain
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DOI no:
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J Biol Chem
291:16840-16848
(2016)
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PubMed id:
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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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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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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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Links
