8qfz
From Proteopedia
(Difference between revisions)
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==TSLP-Bicycle complex== | ==TSLP-Bicycle complex== | ||
| - | <StructureSection load='8qfz' size='340' side='right'caption='[[8qfz]]' scene=''> | + | <StructureSection load='8qfz' size='340' side='right'caption='[[8qfz]], [[Resolution|resolution]] 1.65Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8QFZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8QFZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[8qfz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8QFZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8QFZ FirstGlance]. <br> |
| - | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction</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]] 1.65Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LFI:1-[3,5-bis(3-bromanylpropanoyl)-1,3,5-triazinan-1-yl]-3-bromanyl-propan-1-one'>LFI</scene></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=8qfz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8qfz OCA], [https://pdbe.org/8qfz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8qfz RCSB], [https://www.ebi.ac.uk/pdbsum/8qfz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8qfz ProSAT]</span></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=8qfz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8qfz OCA], [https://pdbe.org/8qfz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8qfz RCSB], [https://www.ebi.ac.uk/pdbsum/8qfz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8qfz ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/TSLP_HUMAN TSLP_HUMAN] Isoform 1: Cytokine that induces the release of T-cell-attracting chemokines from monocytes and, in particular, enhances the maturation of CD11c(+) dendritic cells. Can induce allergic inflammation by directly activating mast cells.<ref>PMID:11418668</ref> <ref>PMID:11480573</ref> <ref>PMID:17242164</ref> Isoform 2: May act as an antimicrobial peptide in the oral cavity and on the skin.<ref>PMID:24850429</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pro-inflammatory cytokine involved in the development of asthma and other atopic diseases. We used Bicycle Therapeutics' proprietary phage display platform to identify bicyclic peptides (Bicycles) with high affinity for TSLP, a target that is difficult to drug with conventional small molecules due to the extended protein-protein interactions it forms with both receptors. The hit series was shown to bind to TSLP in a hotspot, that is also used by IL-7Ralpha. Guided by the first X-ray crystal structure of a small peptide binding to TSLP and the identification of key metabolites, we were able to improve the proteolytic stability of this series in lung S9 fractions without sacrificing binding affinity. This resulted in the potent Bicycle 46 with nanomolar affinity to TSLP (K(D) = 13 nM), low plasma clearance of 6.4 mL/min/kg, and an effective half-life of 46 min after intravenous dosing to rats. | ||
| + | |||
| + | Discovery and Characterization of a Bicyclic Peptide (Bicycle) Binder to Thymic Stromal Lymphopoietin.,Narjes F, Edfeldt F, Petersen J, Oster L, Hamblet C, Bird J, Bold P, Rae R, Back E, Stomilovic S, Zlatoidsky P, Svensson T, Hidestal L, Kunalingam L, Shamovsky I, De Maria L, Gordon E, Lewis RJ, Watcham S, van Rietschoten K, Mudd GE, Harrison H, Chen L, Skynner MJ J Med Chem. 2024 Feb 8;67(3):2220-2235. doi: 10.1021/acs.jmedchem.3c02163. Epub , 2024 Jan 29. PMID:38284169<ref>PMID:38284169</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 8qfz" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Petersen | + | [[Category: Synthetic construct]] |
| + | [[Category: Petersen J]] | ||
Current revision
TSLP-Bicycle complex
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