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4j51
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| - | + | ==Cyrstal structure of protein tyrosine phosphatase Lyp catalytic domain complex with small molecular inhibitor L75N04== | |
| - | + | <StructureSection load='4j51' size='340' side='right' caption='[[4j51]], [[Resolution|resolution]] 2.30Å' scene=''> | |
| - | { | + | == Structural highlights == |
| - | + | <table><tr><td colspan='2'>[[4j51]] is a 2 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=4J51 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4J51 FirstGlance]. <br> | |
| - | ==Disease== | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=N75:3-[(3-CHLOROPHENYL)ETHYNYL]-2-{4-[2-(CYCLOPROPYLAMINO)-2-OXOETHOXY]PHENYL}-6-HYDROXY-1-BENZOFURAN-5-CARBOXYLIC+ACID'>N75</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PTPN22, PTPN8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein-tyrosine-phosphatase Protein-tyrosine-phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.48 3.1.3.48] </span></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=4j51 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j51 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4j51 RCSB], [http://www.ebi.ac.uk/pdbsum/4j51 PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
[[http://www.uniprot.org/uniprot/PTN22_HUMAN PTN22_HUMAN]] Defects in PTPN22 are a cause of susceptibility to systemic lupus erythematosus (SLE) [MIM:[http://omim.org/entry/152700 152700]]. SLE is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. It is thought to represent a failure of the regulatory mechanisms of the autoimmune system.<ref>PMID:15273934</ref> | [[http://www.uniprot.org/uniprot/PTN22_HUMAN PTN22_HUMAN]] Defects in PTPN22 are a cause of susceptibility to systemic lupus erythematosus (SLE) [MIM:[http://omim.org/entry/152700 152700]]. SLE is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. It is thought to represent a failure of the regulatory mechanisms of the autoimmune system.<ref>PMID:15273934</ref> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/PTN22_HUMAN PTN22_HUMAN]] Acts as negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules. Associates with and probably dephosphorylates CBL. Dephosphorylates LCK at its activating 'Tyr-394' residue. Dephosphorylates ZAP70 at its activating 'Tyr-493' residue. Dephosphorylates the immune system activator SKAP2.<ref>PMID:16461343</ref> <ref>PMID:18056643</ref> <ref>PMID:19167335</ref> <ref>PMID:21719704</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Lymphoid-specific tyrosine phosphatase (LYP), a member of the protein tyrosine phosphatase (PTP) family of signaling enzymes, is associated with a broad spectrum of autoimmune diseases. Herein we describe our structure-based lead optimization efforts within a 6-hydroxy-benzofuran-5-carboxylic acid series culminating in the identification of compound 8b, a potent and selective inhibitor of LYP with a Ki value of 110 nM and more than 9-fold selectivity over a large panel of PTPs. The structure of LYP in complex with 8b was obtained by X-ray crystallography, providing detailed information about the molecular recognition of small-molecule ligands binding LYP. Importantly, compound 8b possesses highly efficacious cellular activity in both T- and mast cells and is capable of blocking anaphylaxis in mice. Discovery of 8b establishes a starting point for the development of clinically useful LYP inhibitors for treating a wide range of autoimmune disorders. | ||
| - | + | A Potent and Selective Small-Molecule Inhibitor for the Lymphoid-Specific Tyrosine Phosphatase (LYP), a Target Associated with Autoimmune Diseases.,He Y, Liu S, Menon A, Stanford S, Oppong E, Gunawan AM, Wu L, Wu DJ, Barrios AM, Bottini N, Cato AC, Zhang ZY J Med Chem. 2013 Jun 27;56(12):4990-5008. doi: 10.1021/jm400248c. Epub 2013 Jun, 6. PMID:23713581<ref>PMID:23713581</ref> | |
| - | + | ||
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | == | + | ==See Also== |
| - | + | *[[Tyrosine phosphatase|Tyrosine phosphatase]] | |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein-tyrosine-phosphatase]] | [[Category: Protein-tyrosine-phosphatase]] | ||
| - | [[Category: He, Y | + | [[Category: He, Y]] |
| - | [[Category: Liu, D | + | [[Category: Liu, D]] |
| - | [[Category: Zhang, Z Y | + | [[Category: Zhang, Z Y]] |
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
[[Category: Inhibitor design]] | [[Category: Inhibitor design]] | ||
[[Category: Tyrosine phosphatase]] | [[Category: Tyrosine phosphatase]] | ||
Revision as of 12:38, 21 December 2014
Cyrstal structure of protein tyrosine phosphatase Lyp catalytic domain complex with small molecular inhibitor L75N04
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