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5j13

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Current revision

Structural basis for TSLP antagonism by the therapeutic antibody Tezepelumab (MEDI9929 / AMG-157)

Structural highlights

5j13 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.298Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] ^[3] Isoform 2: May act as an antimicrobial peptide in the oral cavity and on the skin.^[4]

Publication Abstract from PubMed

The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is pivotal to the pathophysiology of widespread allergic diseases mediated by type 2 helper T cell (Th2) responses, including asthma and atopic dermatitis. The emergence of human TSLP as a clinical target against asthma calls for maximally harnessing its therapeutic potential via structural and mechanistic considerations. Here we employ an integrative experimental approach focusing on productive and antagonized TSLP complexes and free cytokine. We reveal how cognate receptor TSLPR allosterically activates TSLP to potentiate the recruitment of the shared interleukin 7 receptor alpha-chain (IL-7Ralpha) by leveraging the flexibility, conformational heterogeneity and electrostatics of the cytokine. We further show that the monoclonal antibody Tezepelumab partly exploits these principles to neutralize TSLP activity. Finally, we introduce a fusion protein comprising a tandem of the TSLPR and IL-7Ralpha extracellular domains, which harnesses the mechanistic intricacies of the TSLP-driven receptor complex to manifest high antagonistic potency.

Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma.,Verstraete K, Peelman F, Braun H, Lopez J, Van Rompaey D, Dansercoer A, Vandenberghe I, Pauwels K, Tavernier J, Lambrecht BN, Hammad H, De Winter H, Beyaert R, Lippens G, Savvides SN Nat Commun. 2017 Apr 3;8:14937. doi: 10.1038/ncomms14937. PMID:28368013^[5]

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

References

↑ Reche PA, Soumelis V, Gorman DM, Clifford T, Liu Mr, Travis M, Zurawski SM, Johnston J, Liu YJ, Spits H, de Waal Malefyt R, Kastelein RA, Bazan JF. Human thymic stromal lymphopoietin preferentially stimulates myeloid cells. J Immunol. 2001 Jul 1;167(1):336-43. PMID:11418668
↑ Quentmeier H, Drexler HG, Fleckenstein D, Zaborski M, Armstrong A, Sims JE, Lyman SD. Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation. Leukemia. 2001 Aug;15(8):1286-92. PMID:11480573
↑ Allakhverdi Z, Comeau MR, Jessup HK, Yoon BR, Brewer A, Chartier S, Paquette N, Ziegler SF, Sarfati M, Delespesse G. Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J Exp Med. 2007 Feb 19;204(2):253-8. Epub 2007 Jan 22. PMID:17242164 doi:http://dx.doi.org/jem.20062211
↑ Bjerkan L, Schreurs O, Engen SA, Jahnsen FL, Baekkevold ES, Blix IJ, Schenck K. The short form of TSLP is constitutively translated in human keratinocytes and has characteristics of an antimicrobial peptide. Mucosal Immunol. 2015 Jan;8(1):49-56. doi: 10.1038/mi.2014.41. Epub 2014 May 21. PMID:24850429 doi:http://dx.doi.org/10.1038/mi.2014.41
↑ Verstraete K, Peelman F, Braun H, Lopez J, Van Rompaey D, Dansercoer A, Vandenberghe I, Pauwels K, Tavernier J, Lambrecht BN, Hammad H, De Winter H, Beyaert R, Lippens G, Savvides SN. Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. Nat Commun. 2017 Apr 3;8:14937. doi: 10.1038/ncomms14937. PMID:28368013 doi:http://dx.doi.org/10.1038/ncomms14937

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5j13"

Categories: Homo sapiens | Large Structures | Savvides SN | Verstraete K

@@ Line 1: / Line 1: @@
 ==Structural basis for TSLP antagonism by the therapeutic antibody Tezepelumab (MEDI9929 / AMG-157)==
-<StructureSection load='5j13' size='340' side='right' caption='[[5j13]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+<StructureSection load='5j13' size='340' side='right'caption='[[5j13]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5j13]] is a 3 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=5J13 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J13 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5j13]] is a 3 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=5J13 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5J13 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.298&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TSLP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=5j13 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j13 OCA], [http://pdbe.org/5j13 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j13 RCSB], [http://www.ebi.ac.uk/pdbsum/5j13 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j13 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=5j13 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j13 OCA], [https://pdbe.org/5j13 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5j13 RCSB], [https://www.ebi.ac.uk/pdbsum/5j13 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5j13 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://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>
+[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 ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Savvides, S N]]
+[[Category: Large Structures]]
-[[Category: Verstraete, K]]
+[[Category: Savvides SN]]
-[[Category: Cytokine inflammation tslp antibody]]
+[[Category: Verstraete K]]
-[[Category: Immune system]]

5j13

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Current revision

Structural basis for TSLP antagonism by the therapeutic antibody Tezepelumab (MEDI9929 / AMG-157)

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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