8skl
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==PTP1B in complex with 182== | |
| + | <StructureSection load='8skl' size='340' side='right'caption='[[8skl]], [[Resolution|resolution]] 1.55Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8skl]] is a 1 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=8SKL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8SKL 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]] 1.55Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=V2O:5-[1-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-1lambda~6~,2,5-thiadiazolidine-1,1,3-trione'>V2O</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=8skl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8skl OCA], [https://pdbe.org/8skl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8skl RCSB], [https://www.ebi.ac.uk/pdbsum/8skl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8skl ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/PTN1_HUMAN PTN1_HUMAN] Tyrosine-protein phosphatase which acts as a regulator of endoplasmic reticulum unfolded protein response. Mediates dephosphorylation of EIF2AK3/PERK; inactivating the protein kinase activity of EIF2AK3/PERK. May play an important role in CKII- and p60c-src-induced signal transduction cascades. May regulate the EFNA5-EPHA3 signaling pathway which modulates cell reorganization and cell-cell repulsion.<ref>PMID:21135139</ref> <ref>PMID:22169477</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The inhibition of protein tyrosine phosphatases (PTPs), such as PTP1B and PTPN2 that function as intracellular checkpoints, has emerged as an exciting new approach for bolstering T cell anti-tumor immunity to combat cancer. ABBV-CLS-484 is a dual PTP1B and PTPN2 inhibitor currently in clinical trials for solid tumors. Here we have explored the therapeutic potential of targeting PTP1B and PTPN2 with a related small molecule inhibitor, Compound 182. We demonstrate that Compound 182 is a highly potent and selective active site competitive inhibitor of PTP1B and PTPN2 that enhances antigen-induced T cell activation and expansion ex vivo and represses the growth of syngeneic tumors in C57BL/6 mice without promoting overt immune-related toxicities. Compound 182 repressed the growth of immunogenic MC38 colorectal and AT3-OVA mammary tumors as well as immunologically cold AT3 mammary tumors that are largely devoid of T cells. Treatment with Compound 182 increased both the infiltration and activation of T cells, as well as the recruitment of NK cells and B cells that promote anti-tumor immunity. The enhanced anti-tumor immunity in immunogenic AT3-OVA tumors could be ascribed largely to the inhibition of PTP1B/PTPN2 in T cells, whereas in cold AT3 tumors, Compound 182 elicited both direct effects on tumor cells and T cells to facilitate T cell recruitment and thereon activation. Importantly, treatment with Compound 182 rendered otherwise resistant AT3 tumors sensitive to anti-PD1 therapy. Our findings establish the potential for small molecule active site inhibitors of PTP1B and PTPN2 to enhance anti-tumor immunity and combat cancer. | ||
| - | + | A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity.,Liang S, Tran E, Du X, Dong J, Sudholz H, Chen H, Qu Z, Huntington N, Babon J, Kershaw N, Zhang ZY, Baell J, Wiede F, Tiganis T bioRxiv. 2023 Jun 28:2023.06.16.545220. doi: 10.1101/2023.06.16.545220. Preprint. PMID:37397992<ref>PMID:37397992</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 8skl" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Babon JJ]] | ||
| + | [[Category: Chen H]] | ||
| + | [[Category: Tiganis T]] | ||
Revision as of 10:41, 2 August 2023
PTP1B in complex with 182
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