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| | ==Crystal structure of EBI-005, a chimera of human IL-1beta and IL-1Ra, bound to human Interleukin-1 receptor type 1== | | ==Crystal structure of EBI-005, a chimera of human IL-1beta and IL-1Ra, bound to human Interleukin-1 receptor type 1== |
| - | <StructureSection load='4gaf' size='340' side='right' caption='[[4gaf]], [[Resolution|resolution]] 2.15Å' scene=''> | + | <StructureSection load='4gaf' size='340' side='right'caption='[[4gaf]], [[Resolution|resolution]] 2.15Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4gaf]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GAF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GAF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4gaf]] is a 2 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=4GAF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GAF FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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]] 2.15Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gai|4gai]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IL1R1, IL1R, IL1RA, IL1RT1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4gaf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gaf OCA], [https://pdbe.org/4gaf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gaf RCSB], [https://www.ebi.ac.uk/pdbsum/4gaf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gaf ProSAT]</span></td></tr> |
| - | <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://pdbe.org/4gaf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4gaf RCSB], [http://www.ebi.ac.uk/pdbsum/4gaf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4gaf ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == 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> | + | [https://www.uniprot.org/uniprot/IL1B_HUMAN 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.<ref>PMID:3920526</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4gaf" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4gaf" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Interleukin receptor 3D structures|Interleukin receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Barnes, T M]] | + | [[Category: Large Structures]] |
| - | [[Category: Furfine, E S]] | + | [[Category: Barnes TM]] |
| - | [[Category: Garcia, K C]] | + | [[Category: Furfine ES]] |
| - | [[Category: Hou, J]] | + | [[Category: Garcia KC]] |
| - | [[Category: Kiner, O]] | + | [[Category: Hou J]] |
| - | [[Category: King, B]] | + | [[Category: Kiner O]] |
| - | [[Category: Kovalchin, J T]] | + | [[Category: King B]] |
| - | [[Category: Masci, A]] | + | [[Category: Kovalchin JT]] |
| - | [[Category: Shu, Y]] | + | [[Category: Masci A]] |
| - | [[Category: Thomas, C]] | + | [[Category: Shu Y]] |
| - | [[Category: Townson, S A]] | + | [[Category: Thomas C]] |
| - | [[Category: Beta-trefoil]]
| + | [[Category: Townson SA]] |
| - | [[Category: Il-1 signaling]]
| + | |
| - | [[Category: Il-1beta]]
| + | |
| - | [[Category: Il-1r1]]
| + | |
| - | [[Category: Il-1ra]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| Structural highlights
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
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.
See Also
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
- ↑ 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
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