5veb: Difference between revisions
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==Crystal structure of a Fab binding to extracellular domain 5 of Cadherin-6== | ==Crystal structure of a Fab binding to extracellular domain 5 of Cadherin-6== | ||
<StructureSection load='5veb' size='340' side='right' caption='[[5veb]], [[Resolution|resolution]] 2.34Å' scene=''> | <StructureSection load='5veb' size='340' side='right'caption='[[5veb]], [[Resolution|resolution]] 2.34Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5veb]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VEB OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[5veb]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VEB OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5VEB FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A2G:N-ACETYL-2-DEOXY-2-AMINO-GALACTOSE'>A2G</scene>, <scene name='pdbligand=SIN:SUCCINIC+ACID'>SIN</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A2G:N-ACETYL-2-DEOXY-2-AMINO-GALACTOSE'>A2G</scene>, <scene name='pdbligand=SIN:SUCCINIC+ACID'>SIN</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5veb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5veb OCA], [http://pdbe.org/5veb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5veb RCSB], [http://www.ebi.ac.uk/pdbsum/5veb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5veb ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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</div> | </div> | ||
<div class="pdbe-citations 5veb" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5veb" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Cadherin 3D structures|Cadherin 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | |||
[[Category: Bialucha, C U]] | [[Category: Bialucha, C U]] | ||
[[Category: Clark, K]] | [[Category: Clark, K]] | ||
Latest revision as of 11:35, 30 September 2020
Crystal structure of a Fab binding to extracellular domain 5 of Cadherin-6Crystal structure of a Fab binding to extracellular domain 5 of Cadherin-6
Structural highlights
Function[CADH6_HUMAN] Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. Publication Abstract from PubMedDespite an improving therapeutic landscape, significant challenges remain in treating the majority of patients with advanced ovarian or renal cancer. We identified the cell-cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancers. HKT288 is an optimized CDH6-targeting DM4-based antibody-drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal antitumor activity and highlights CDH6 as an antigen for biotherapeutic development. To more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models-a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models in vivo, including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation.Significance: We identify CDH6 as a target for biotherapeutics development and demonstrate how an integrated pharmacology strategy that incorporates mechanistic pharmacodynamics and toxicology studies provides a rich dataset for optimizing the therapeutic format. We highlight how a population-based PDX clinical trial and retrospective biomarker analysis can provide correlates of activity and response to guide initial patient selection for first-in-human trials of HKT288. Cancer Discov; 7(9); 1030-45. (c)2017 AACR.This article is highlighted in the In This Issue feature, p. 920. Discovery and Optimization of HKT288, a Cadherin-6-Targeting ADC for the Treatment of Ovarian and Renal Cancers.,Bialucha CU, Collins SD, Li X, Saxena P, Zhang X, Durr C, Lafont B, Prieur P, Shim Y, Mosher R, Lee D, Ostrom L, Hu T, Bilic S, Rajlic IL, Capka V, Jiang W, Wagner JP, Elliott G, Veloso A, Piel JC, Flaherty MM, Mansfield KG, Meseck EK, Rubic-Schneider T, London AS, Tschantz WR, Kurz M, Nguyen D, Bourret A, Meyer MJ, Faris JE, Janatpour MJ, Chan VW, Yoder NC, Catcott KC, McShea MA, Sun X, Gao H, Williams J, Hofmann F, Engelman JA, Ettenberg SA, Sellers WR, Lees E Cancer Discov. 2017 Sep;7(9):1030-1045. doi: 10.1158/2159-8290.CD-16-1414. Epub, 2017 May 19. PMID:28526733[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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