7d85: Difference between revisions
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The | ==Crystal structure of anti-ErbB3 Fab ISU104 in complex with human ErbB3 extracellular domain 3== | ||
<StructureSection load='7d85' size='340' side='right'caption='[[7d85]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7d85]] 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=7D85 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7D85 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]] 2.5Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=7d85 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d85 OCA], [https://pdbe.org/7d85 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7d85 RCSB], [https://www.ebi.ac.uk/pdbsum/7d85 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7d85 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/ERBB3_HUMAN ERBB3_HUMAN] Defects in ERBB3 are the cause of lethal congenital contracture syndrome type 2 (LCCS2) [MIM:[https://omim.org/entry/607598 607598]; also called Israeli Bedouin multiple contracture syndrome type A. LCCS2 is an autosomal recessive neurogenic form of a neonatally lethal arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord. The LCCS2 syndrome is characterized by multiple joint contractures, anterior horn atrophy in the spinal cord, and a unique feature of a markedly distended urinary bladder. The phenotype suggests a spinal cord neuropathic etiology.<ref>PMID:17701904</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/ERBB3_HUMAN ERBB3_HUMAN] Binds and is activated by neuregulins and NTAK.<ref>PMID:15358134</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
ErbB3, a member of the ErbB receptor family, is a potent mediator in the development and progression of cancer, and its activation plays pivotal roles in acquired resistance against anti-EGFR therapies and other standard-of-care therapies. Upon ligand (NRG1) binding, ErbB3 forms heterodimers with other ErbB proteins (i.e., EGFR and ErbB2), which allows activation of downstream PI3K/Akt signaling. In this study, we developed a fully human anti-ErbB3 antibody, named ISU104, as an anticancer agent. ISU104 binds potently and specifically to the domain 3 of ErbB3. The complex structure of ErbB3-domain 3::ISU104-Fab revealed that ISU104 binds to the NRG1 binding region of domain 3. The elucidated structure suggested that the binding of ISU104 to ErbB3 would hinder not only ligand binding but also the structural changes required for heterodimerization. Biochemical studies confirmed these predictions. ISU104 inhibited ligand binding, ligand-dependent heterodimerization and phosphorylation, and induced the internalization of ErbB3. As a result, downstream Akt phosphorylation and cell proliferation were inhibited. The anticancer efficacy of ISU104 was demonstrated in xenograft models of various cancers. In summary, a highly potent ErbB3 targeting antibody, ISU104, is suitable for clinical development. | |||
A Novel Therapeutic Anti-ErbB3, ISU104 Exhibits Potent Antitumorigenic Activity by Inhibiting Ligand Binding and ErbB3 Heterodimerization.,Hong M, Yoo Y, Kim M, Kim JY, Cha JS, Choi MK, Kim U, Kim K, Sohn Y, Bae D, Cho HS, Hong SB Mol Cancer Ther. 2021 Jun;20(6):1142-1152. doi: 10.1158/1535-7163.MCT-20-0907. , Epub 2021 Mar 29. PMID:33782100<ref>PMID:33782100</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Cho | <div class="pdbe-citations 7d85" style="background-color:#fffaf0;"></div> | ||
[[Category: Yoo | |||
==See Also== | |||
*[[Antibody 3D structures|Antibody 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Cho HS]] | |||
[[Category: Yoo Y]] | |||