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{{STRUCTURE_4gaf|  PDB=4gaf  |  SCENE=  }}
==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]] 2.15&Aring;' scene=''>
{{ABSTRACT_PUBMED_23431173}}
== Structural highlights ==
<table><tr><td colspan='2'>[[4gaf]] is a 2 chain structure with sequence from [http://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 [http://oca.weizmann.ac.il/oca-docs/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>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gai|4gai]]</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 Homo sapiens])</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://www.rcsb.org/pdb/explore.do?structureId=4gaf RCSB], [http://www.ebi.ac.uk/pdbsum/4gaf PDBsum]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== 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.


==Function==
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<ref>PMID:23431173</ref>
[[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>  


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[4gaf]] is a 2 chain structure with sequence from [http://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].
</div>


==Reference==
==See Also==
<references group="xtra"/><references/>
*[[Interleukin receptor|Interleukin receptor]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Barnes, T M.]]
[[Category: Barnes, T M]]
[[Category: Furfine, E S.]]
[[Category: Furfine, E S]]
[[Category: Garcia, K C.]]
[[Category: Garcia, K C]]
[[Category: Hou, J.]]
[[Category: Hou, J]]
[[Category: Kiner, O.]]
[[Category: Kiner, O]]
[[Category: King, B.]]
[[Category: King, B]]
[[Category: Kovalchin, J T.]]
[[Category: Kovalchin, J T]]
[[Category: Masci, A.]]
[[Category: Masci, A]]
[[Category: Shu, Y.]]
[[Category: Shu, Y]]
[[Category: Thomas, C.]]
[[Category: Thomas, C]]
[[Category: Townson, S A.]]
[[Category: Townson, S A]]
[[Category: Beta-trefoil]]
[[Category: Beta-trefoil]]
[[Category: Il-1 signaling]]
[[Category: Il-1 signaling]]

Revision as of 11:31, 21 December 2014

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

4gaf, resolution 2.15Å

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