9wwh: Difference between revisions

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'''Unreleased structure'''


The entry 9wwh is ON HOLD  until Paper Publication
==Crystal structure of IL-33 and antibody Tozorakimab fab binary complex==
<StructureSection load='9wwh' size='340' side='right'caption='[[9wwh]], [[Resolution|resolution]] 3.51&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9wwh]] is a 6 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=9WWH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9WWH FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.51&#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=9wwh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9wwh OCA], [https://pdbe.org/9wwh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9wwh RCSB], [https://www.ebi.ac.uk/pdbsum/9wwh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9wwh ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/IL33_HUMAN IL33_HUMAN] Cytokine that binds to and signals through IL1RL1/ST2 and its stimulation recruits MYD88, IRAK1, IRAK4, and TRAF6, followed by phosphorylation of MAPK3/ERK1 and/or MAPK1/ERK2, MAPK14, and MAPK8. Induces T-helper type 2-associated cytokines. Acts as a chemoattractant tor Th2 cells, and may function as an "alarmin", that amplifies immune responses during tissue injury.<ref>PMID:16286016</ref> <ref>PMID:17853410</ref> <ref>PMID:17185418</ref> <ref>PMID:18787100</ref> <ref>PMID:18836528</ref> <ref>PMID:21734074</ref> <ref>PMID:22215666</ref>  In quiescent endothelia the uncleaved form is constitutively and abundantly expressed, and acts as a chromatin-associated nuclear factor with transcriptional repressor properties, it may sequester nuclear NF-kappaB/RELA, lowering expression of its targets. This form is rapidely lost upon angiogenic or proinflammatory activation.<ref>PMID:16286016</ref> <ref>PMID:17853410</ref> <ref>PMID:17185418</ref> <ref>PMID:18787100</ref> <ref>PMID:18836528</ref> <ref>PMID:21734074</ref> <ref>PMID:22215666</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Interleukin-33 (IL-33), an alarmin cytokine of the IL-1 family, drives type 2 inflammation through signaling via the ST2 and IL-1RAcP receptors, making it a critical therapeutic target for inflammatory diseases such as asthma and chronic obstructive pulmonary disease. Current therapeutic strategies have primarily focused on antibodies that target IL-33 or ST2 to disrupt their specific interaction. However, the structural mechanisms underlying antibody-mediated neutralization of IL-33 remain poorly understood. Here, we report the structures of three antibodies in clinical trial - etokimab, itepekimab, and tozorakimab - complexed with IL-33, determined by X-ray crystallography and cryo-electron microscopy. Structural analysis reveals two distinct neutralizing epitopes on IL-33, termed Epitope 1 at IL-33/ST2 binding Site 1 and Epitope 2 at IL-33/ST2 binding Site 2. Tozorakimab, which targets Epitope 1, completely blocks ST2 engagement by sterically occluding the ST2 D1-D2 domain-binding interface. In contrast, etokimab and itepekimab, which recognize Epitope 2, interfere with IL-33 recognition of the ST2 D3 domain and thereby only partially inhibit ST2 binding. These structural and biochemical findings provide a molecular explanation for the differential efficacy of the three antibodies in inhibiting IL-33 signaling in cellular assays. Collectively, our results provide valuable insights into the molecular determinants of efficacy for existing IL-33 therapeutics and offer a structural framework for the rational design of next-generation IL-33 targeted inhibitors.


Authors: Wang, X.Q., Chen, J., Wang, Y.
Structures of clinical antibodies bound to IL-33 uncover two distinct epitopes underlying differential efficacy.,Chen J, Wang Y, Wang X MAbs. 2026 Dec;18(1):2639673. doi: 10.1080/19420862.2026.2639673. Epub 2026 Mar , 1. PMID:41765683<ref>PMID:41765683</ref>


Description: Crystal structure of IL-33 and antibody Tozorakimab fab binary complex
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Wang, X.Q]]
<div class="pdbe-citations 9wwh" style="background-color:#fffaf0;"></div>
[[Category: Wang, Y]]
== References ==
[[Category: Chen, J]]
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chen J]]
[[Category: Wang XQ]]
[[Category: Wang Y]]
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