4g6j

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of human IL-1beta in complex with the therapeutic antibody binding fragment of canakinumab

Structural highlights

4g6j is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.03Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

IL1B_HUMAN Produced by activated macrophages, IL-1 stimulates thymocyte proliferation by inducing IL-2 release, B-cell maturation and proliferation, and fibroblast growth factor activity. IL-1 proteins are involved in the inflammatory response, being identified as endogenous pyrogens, and are reported to stimulate the release of prostaglandin and collagenase from synovial cells.^[1]

Publication Abstract from PubMed

Interleukin-1beta (IL-1beta) is a key orchestrator in inflammatory and several immune responses. IL-1beta 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-1beta monoclonal antibodies. Canakinumab is known to neutralize IL-1beta 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-1beta bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1beta 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-1beta. Furthermore, we characterized the epitopes on IL-1beta 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-1beta and provide insight into the mechanisms leading to their distinct modulation of IL-1beta signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1beta causes competitive inhibition of the association of IL-1beta and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1beta and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1beta pathway attenuation.

One Target-Two Different Binding Modes: Structural Insights into Gevokizumab and Canakinumab Interactions to Interleukin-1beta,Blech M, Peter D, Fischer P, Bauer MM, Hafner M, Zeeb M, Nar H J Mol Biol. 2012 Oct 3. pii: S0022-2836(12)00786-3. doi:, 10.1016/j.jmb.2012.09.021. PMID:23041424^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Van Damme J, De Ley M, Opdenakker G, Billiau A, De Somer P, Van Beeumen J. Homogeneous interferon-inducing 22K factor is related to endogenous pyrogen and interleukin-1. Nature. 1985 Mar 21-27;314(6008):266-8. PMID:3920526
↑ Blech M, Peter D, Fischer P, Bauer MM, Hafner M, Zeeb M, Nar H. One Target-Two Different Binding Modes: Structural Insights into Gevokizumab and Canakinumab Interactions to Interleukin-1beta J Mol Biol. 2012 Oct 3. pii: S0022-2836(12)00786-3. doi:, 10.1016/j.jmb.2012.09.021. PMID:23041424 doi:10.1016/j.jmb.2012.09.021

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4g6j"

Categories: Homo sapiens | Large Structures | Blech M | Hoerer S

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4g6j]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4G6J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4G6J FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4g6j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g6j OCA], [https://pdbe.org/4g6j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4g6j RCSB], [https://www.ebi.ac.uk/pdbsum/4g6j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4g6j ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.03&#8491;</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4g6j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g6j OCA], [https://pdbe.org/4g6j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4g6j RCSB], [https://www.ebi.ac.uk/pdbsum/4g6j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4g6j ProSAT]</span></td></tr>
 </table>
 == Function ==

4g6j

From Proteopedia

Current revision

Crystal structure of human IL-1beta in complex with the therapeutic antibody binding fragment of canakinumab

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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