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| | ==X-Ray Characterization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors== | | ==X-Ray Characterization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors== |
| - | <StructureSection load='5ovr' size='340' side='right' caption='[[5ovr]], [[Resolution|resolution]] 2.15Å' scene=''> | + | <StructureSection load='5ovr' size='340' side='right'caption='[[5ovr]], [[Resolution|resolution]] 2.15Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ovr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OVR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OVR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ovr]] 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=5OVR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OVR FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AXK:[(~{S})-[4-[3-[(~{R})-(3,4-dichlorophenyl)-oxidanyl-methyl]phenyl]phenyl]-oxidanyl-methyl]phosphonic+acid'>AXK</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.15Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AXK:[(~{S})-[4-[3-[(~{R})-(3,4-dichlorophenyl)-oxidanyl-methyl]phenyl]phenyl]-oxidanyl-methyl]phosphonic+acid'>AXK</scene>, <scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PTPN5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5ovr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ovr OCA], [https://pdbe.org/5ovr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ovr RCSB], [https://www.ebi.ac.uk/pdbsum/5ovr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ovr ProSAT]</span></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>
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| - | <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=5ovr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ovr OCA], [http://pdbe.org/5ovr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ovr RCSB], [http://www.ebi.ac.uk/pdbsum/5ovr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ovr ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PTN5_HUMAN PTN5_HUMAN]] May regulate the activity of several effector molecules involved in synaptic plasticity and neuronal cell survival, including MAPKs, Src family kinases and NMDA receptors.<ref>PMID:21777200</ref> | + | [https://www.uniprot.org/uniprot/PTN5_HUMAN PTN5_HUMAN] May regulate the activity of several effector molecules involved in synaptic plasticity and neuronal cell survival, including MAPKs, Src family kinases and NMDA receptors.<ref>PMID:21777200</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5ovr" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5ovr" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Tyrosine phosphatase 3D structures|Tyrosine phosphatase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Protein-tyrosine-phosphatase]] | + | [[Category: Large Structures]] |
| - | [[Category: Kack, H]] | + | [[Category: Kack H]] |
| - | [[Category: Wissler, L]] | + | [[Category: Wissler L]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Phosphatase alzheimer's disease inhibitor step]]
| + | |
| Structural highlights
Function
PTN5_HUMAN May regulate the activity of several effector molecules involved in synaptic plasticity and neuronal cell survival, including MAPKs, Src family kinases and NMDA receptors.[1]
Publication Abstract from PubMed
Excessive activity of striatal-enriched protein tyrosine phosphatase (STEP) in the brain has been detected in numerous neuropsychiatric disorders including Alzheimer's disease. Notably, knockdown of STEP in an Alzheimer mouse model effected an increase in the phosphorylation levels of downstream STEP substrates and a significant reversal in the observed cognitive and memory deficits. These data point to the promising potential of STEP as a target for drug discovery in Alzheimer's treatment. We previously reported a substrate-based approach to the development of low molecular weight STEP inhibitors with Ki values as low as 7.8 muM. Herein, we disclose the first X-ray crystal structures of inhibitors bound to STEP and the surprising finding that they occupy noncoincident binding sites. Moreover, we utilize this structural information to optimize the inhibitor structure to achieve a Ki of 110 nM, with 15-60-fold selectivity across a series of phosphatases.
X-ray Characterization and Structure-Based Optimization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors.,Witten MR, Wissler L, Snow M, Geschwindner S, Read JA, Brandon NJ, Nairn AC, Lombroso PJ, Kack H, Ellman JA J Med Chem. 2017 Nov 8. doi: 10.1021/acs.jmedchem.7b01292. PMID:29116812[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mukherjee S, Poddar R, Deb I, Paul S. Dephosphorylation of specific sites in the kinase-specificity sequence domain leads to ubiquitin-mediated degradation of the tyrosine phosphatase STEP. Biochem J. 2011 Nov 15;440(1):115-25. doi: 10.1042/BJ20110240. PMID:21777200 doi:http://dx.doi.org/10.1042/BJ20110240
- ↑ Witten MR, Wissler L, Snow M, Geschwindner S, Read JA, Brandon NJ, Nairn AC, Lombroso PJ, Kack H, Ellman JA. X-ray Characterization and Structure-Based Optimization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors. J Med Chem. 2017 Nov 8. doi: 10.1021/acs.jmedchem.7b01292. PMID:29116812 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01292
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