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4gaf

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Revision as of 10:00, 25 December 2014

Crystal structure of EBI-005, a chimera of human IL-1beta and IL-1Ra, bound to human Interleukin-1 receptor type 1

Structural highlights

4gaf is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	4gai
Gene:	IL1R1, IL1R, IL1RA, IL1RT1 (Homo sapiens)
Resources:	FirstGlance, OCA, RCSB, PDBsum

Function

[IL1R1_HUMAN] Receptor for IL1A, IL1B and IL1RN. After binding to interleukin-1 associates with the corecptor IL1RAP to form the high affinity interleukin-1 receptor complex which mediates interleukin-1-dependent activation of NF-kappa-B, MAPK and other pathways. Signaling involves the recruitment of adapter molecules such as TOLLIP, MYD88, and IRAK1 or IRAK2 via the respective TIR domains of the receptor/coreceptor subunits. Binds ligands with comparable affinity and binding of antagonist IL1RN prevents association with IL1RAP to form a signaling complex.^[1]

Publication Abstract from PubMed

IL-1 is a key inflammatory and immune mediator in many diseases, including dry-eye disease, and its inhibition is clinically efficacious in rheumatoid arthritis and cryopyrin-associated periodic syndromes. To treat ocular surface disease with a topical biotherapeutic, the uniqueness of the site necessitates consideration of the agent's size, target location, binding kinetics, and thermal stability. Here we chimerized two IL-1 receptor ligands, IL-1beta and IL-1Ra, to create an optimized receptor antagonist, EBI-005, for topical ocular administration. EBI-005 binds its target, IL-1R1, 85-fold more tightly than IL-1Ra, and this increase translates to an approximately 100-fold increase in potency in vivo. EBI-005 preserves the affinity bias of IL-1Ra for IL-1R1 over the decoy receptor (IL-1R2), and, surprisingly, is also more thermally stable than either parental molecule. This rationally designed antagonist represents a unique approach to therapeutic design that can potentially be exploited for other beta-trefoil family proteins in the IL-1 and FGF families.

Design of a superior cytokine antagonist for topical ophthalmic use.,Hou J, Townson SA, Kovalchin JT, Masci A, Kiner O, Shu Y, King BM, Schirmer E, Golden K, Thomas C, Garcia KC, Zarbis-Papastoitsis G, Furfine ES, Barnes TM Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3913-8. doi:, 10.1073/pnas.1217996110. Epub 2013 Feb 19. PMID:23431173^[2]

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

References

↑ Slack JL, Schooley K, Bonnert TP, Mitcham JL, Qwarnstrom EE, Sims JE, Dower SK. Identification of two major sites in the type I interleukin-1 receptor cytoplasmic region responsible for coupling to pro-inflammatory signaling pathways. J Biol Chem. 2000 Feb 18;275(7):4670-8. PMID:10671496
↑ Hou J, Townson SA, Kovalchin JT, Masci A, Kiner O, Shu Y, King BM, Schirmer E, Golden K, Thomas C, Garcia KC, Zarbis-Papastoitsis G, Furfine ES, Barnes TM. Design of a superior cytokine antagonist for topical ophthalmic use. Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3913-8. doi:, 10.1073/pnas.1217996110. Epub 2013 Feb 19. PMID:23431173 doi:http://dx.doi.org/10.1073/pnas.1217996110

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/4gaf"

@@ Line 8: / Line 8: @@
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4gaf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gaf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gaf RCSB], [http://www.ebi.ac.uk/pdbsum/4gaf PDBsum]</span></td></tr>
 </table>
+== Function ==
+[[http://www.uniprot.org/uniprot/IL1R1_HUMAN IL1R1_HUMAN]] Receptor for IL1A, IL1B and IL1RN. After binding to interleukin-1 associates with the corecptor IL1RAP to form the high affinity interleukin-1 receptor complex which mediates interleukin-1-dependent activation of NF-kappa-B, MAPK and other pathways. Signaling involves the recruitment of adapter molecules such as TOLLIP, MYD88, and IRAK1 or IRAK2 via the respective TIR domains of the receptor/coreceptor subunits. Binds ligands with comparable affinity and binding of antagonist IL1RN prevents association with IL1RAP to form a signaling complex.<ref>PMID:10671496</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

4gaf

From Proteopedia

Revision as of 10:00, 25 December 2014

Crystal structure of EBI-005, a chimera of human IL-1beta and IL-1Ra, bound to human Interleukin-1 receptor type 1

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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