7e72

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Current revision (16:48, 29 November 2023) (edit) (undo)
 
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==Crystal structure of Tie2-agonistic antibody in complex with human Tie2 Fn2-3==
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<StructureSection load='7e72' size='340' side='right'caption='[[7e72]]' scene=''>
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<StructureSection load='7e72' size='340' side='right'caption='[[7e72]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7e72]] 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=7E72 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E72 FirstGlance]. <br>
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</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=7e72 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e72 OCA], [https://pdbe.org/7e72 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e72 RCSB], [https://www.ebi.ac.uk/pdbsum/7e72 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e72 ProSAT]</span></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.094&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7e72 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e72 OCA], [https://pdbe.org/7e72 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e72 RCSB], [https://www.ebi.ac.uk/pdbsum/7e72 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e72 ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/TIE2_HUMAN TIE2_HUMAN] Defects in TEK are a cause of dominantly inherited venous malformations (VMCM) [MIM:[https://omim.org/entry/600195 600195]; an error of vascular morphogenesis characterized by dilated, serpiginous channels.<ref>PMID:18366015</ref> <ref>PMID:20651738</ref> <ref>PMID:8980225</ref> <ref>PMID:10369874</ref> <ref>PMID:19888299</ref> Note=May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation.<ref>PMID:18366015</ref> <ref>PMID:20651738</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/TIE2_HUMAN TIE2_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post-natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1.<ref>PMID:9204896</ref> <ref>PMID:12816861</ref> <ref>PMID:15284220</ref> <ref>PMID:14665640</ref> <ref>PMID:15851516</ref> <ref>PMID:18425120</ref> <ref>PMID:18425119</ref> <ref>PMID:19223473</ref> <ref>PMID:18366015</ref> <ref>PMID:20651738</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Angiopoietin (Angpt)-Tie receptor 2 (Tie2) plays key roles in vascular development and homeostasis as well as pathological vascular remodeling. Therefore, Tie2-agonistic antibody and engineered Angpt1 variants have been developed as potential therapeutics for ischemic and inflammatory vascular diseases. However, their underlying mechanisms for Tie2 clustering and activation remain elusive and the poor manufacturability and stability of Angpt1 variants limit their clinical application. Here, we develop a human Tie2-agonistic antibody (hTAAB), which targets the membrane proximal fibronectin type III domain of Tie2 distinct from the Angpt-binding site. Our Tie2/hTAAB complex structures reveal that hTAAB tethers the preformed Tie2 homodimers into polygonal assemblies through specific binding to Tie2 Fn3 domain. Notably, the polygonal Tie2 clustering induced by hTAAB is critical for Tie2 activation and are resistant to antagonism by Angpt2. Our results provide insight into the molecular mechanism of Tie2 clustering and activation mediated by hTAAB, and the structure-based humanization of hTAAB creates a potential clinical application.
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Structural insights into the clustering and activation of Tie2 receptor mediated by Tie2 agonistic antibody.,Jo G, Bae J, Hong HJ, Han AR, Kim DK, Hong SP, Kim JA, Lee S, Koh GY, Kim HM Nat Commun. 2021 Nov 1;12(1):6287. doi: 10.1038/s41467-021-26620-1. PMID:34725372<ref>PMID:34725372</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7e72" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Antibody 3D structures|Antibody 3D structures]]
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Z-disk]]
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[[Category: Han A]]
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[[Category: Hong HJ]]
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[[Category: Jo GH]]
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[[Category: Kim HM]]

Current revision

Crystal structure of Tie2-agonistic antibody in complex with human Tie2 Fn2-3

PDB ID 7e72

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