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PDBsum entry 4g6m
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Immune system
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PDB id
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4g6m
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Contents |
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150 a.a.
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220 a.a.
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213 a.a.
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PDB id:
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| Name: |
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Immune system
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Title:
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Crystal structure of human il-1beta in complex with therapeutic antibody binding fragment of gevokizumab
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Structure:
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Interleukin-1 beta. Chain: a. Fragment: unp residues 117-267. Synonym: il-1 beta, catabolin. Engineered: yes. Heavy chain of gevokizumab antibody binding fragment. Chain: h. Engineered: yes. Light chain of gevokizumab antibody binding fragment.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: cho. Homo sapiens, mus musculus. Human, mouse. Organism_taxid: 9606, 10090.
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Resolution:
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1.81Å
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R-factor:
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0.203
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R-free:
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0.226
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Authors:
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M.Blech,S.Hoerer
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Key ref:
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M.Blech
et al.
(2013).
One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β.
J Mol Biol,
425,
94.
PubMed id:
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Date:
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19-Jul-12
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Release date:
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19-Dec-12
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PROCHECK
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Headers
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References
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P01584
(IL1B_HUMAN) -
Interleukin-1 beta from Homo sapiens
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Seq:
Struc:
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269 a.a.
150 a.a.
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J Mol Biol
425:94
(2013)
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PubMed id:
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One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β.
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M.Blech,
D.Peter,
P.Fischer,
M.M.Bauer,
M.Hafner,
M.Zeeb,
H.Nar.
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ABSTRACT
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Interleukin-1β (IL-1β) is a key orchestrator in inflammatory and several
immune responses. IL-1β exerts its effects through interleukin-1 receptor type
I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which
together form a heterotrimeric signaling-competent complex. Canakinumab and
gevokizumab are highly specific IL-1β monoclonal antibodies. Canakinumab is
known to neutralize IL-1β by competing for binding to IL-1R and therefore
blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be
a regulatory therapeutic antibody that modulates IL-1β bioactivity by reducing
the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1β signaling is
affected by both canakinumab and gevokizumab was not yet experimentally
determined. We have analyzed the crystal structures of canakinumab and
gevokizumab antibody binding fragment (Fab) as well as of their binary complexes
with IL-1β. Furthermore, we characterized the epitopes on IL-1β employed by
the antibodies by NMR epitope mapping studies. The direct comparison of NMR and
X-ray data shows that the epitope defined by the crystal structure encompasses
predominantly those residues whose NMR resonances are severely perturbed upon
complex formation. The antigen:Fab co-structures confirm the previously
identified key contact residues on IL-1β and provide insight into the
mechanisms leading to their distinct modulation of IL-1β signaling. A
significant steric overlap of the binding interfaces of IL-1R and canakinumab on
IL-1β causes competitive inhibition of the association of IL-1β and its
receptor. In contrast, gevokizumab occupies an allosteric site on IL-1β and
complex formation results in a minor reduction of binding affinity to IL-1RI.
This suggests two different mechanisms of IL-1β pathway attenuation.
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Links
