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| | ==Crystal structure of bovine low molecular weight protein tyrosine phosphatase (LMPTP) mutant (W49Y N50E) complexed with vanadate and uncompetitive inhibitor== | | ==Crystal structure of bovine low molecular weight protein tyrosine phosphatase (LMPTP) mutant (W49Y N50E) complexed with vanadate and uncompetitive inhibitor== |
| - | <StructureSection load='5jnw' size='340' side='right' caption='[[5jnw]], [[Resolution|resolution]] 1.86Å' scene=''> | + | <StructureSection load='5jnw' size='340' side='right'caption='[[5jnw]], [[Resolution|resolution]] 1.86Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5jnw]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Bovin Bovin]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JNW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5JNW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5jnw]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JNW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JNW FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6LJ:2-(4-{[3-(PIPERIDIN-1-YL)PROPYL]AMINO}QUINOLIN-2-YL)BENZONITRILE'>6LJ</scene>, <scene name='pdbligand=VO4:VANADATE+ION'>VO4</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]] 1.86Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5jnr|5jnr]], [[5jns|5jns]], [[5jnt|5jnt]], [[5jnu|5jnu]], [[5jnv|5jnv]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6LJ:2-(4-{[3-(PIPERIDIN-1-YL)PROPYL]AMINO}QUINOLIN-2-YL)BENZONITRILE'>6LJ</scene>, <scene name='pdbligand=VO4:VANADATE+ION'>VO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ACP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9913 BOVIN])</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=5jnw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jnw OCA], [https://pdbe.org/5jnw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5jnw RCSB], [https://www.ebi.ac.uk/pdbsum/5jnw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5jnw 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>
| + | |
| - | <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=5jnw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jnw OCA], [http://pdbe.org/5jnw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5jnw RCSB], [http://www.ebi.ac.uk/pdbsum/5jnw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5jnw ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PPAC_BOVIN PPAC_BOVIN]] Acts on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates. | + | [https://www.uniprot.org/uniprot/PPAC_BOVIN PPAC_BOVIN] Acts on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates. |
| | <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 5jnw" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5jnw" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Tyrosine phosphatase 3D structures|Tyrosine phosphatase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bovin]] | + | [[Category: Bos taurus]] |
| - | [[Category: Protein-tyrosine-phosphatase]] | + | [[Category: Large Structures]] |
| - | [[Category: Aleshin, A E]] | + | [[Category: Aleshin AE]] |
| - | [[Category: Bankston, L]] | + | [[Category: Bankston L]] |
| - | [[Category: Bottini, N]] | + | [[Category: Bottini N]] |
| - | [[Category: Cadwell, G]] | + | [[Category: Cadwell G]] |
| - | [[Category: Liddington, R C]] | + | [[Category: Liddington RC]] |
| - | [[Category: Stanford, S M]] | + | [[Category: Stanford SM]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Lmptp]]
| + | |
| - | [[Category: Lmw-ptp]]
| + | |
| - | [[Category: Protein tyrosine phosphatase]]
| + | |
| Structural highlights
Function
PPAC_BOVIN Acts on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates.
Publication Abstract from PubMed
Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, and it increases liver IR phosphorylation in vivo and reverses high-fat diet-induced diabetes. Our findings suggest that LMPTP is a key promoter of insulin resistance and that LMPTP inhibitors would be beneficial for treating type 2 diabetes.
Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase.,Stanford SM, Aleshin AE, Zhang V, Ardecky RJ, Hedrick MP, Zou J, Ganji SR, Bliss MR, Yamamoto F, Bobkov AA, Kiselar J, Liu Y, Cadwell GW, Khare S, Yu J, Barquilla A, Chung TD, Mustelin T, Schenk S, Bankston LA, Liddington RC, Pinkerton AB, Bottini N Nat Chem Biol. 2017 Mar 27. doi: 10.1038/nchembio.2344. PMID:28346406[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Stanford SM, Aleshin AE, Zhang V, Ardecky RJ, Hedrick MP, Zou J, Ganji SR, Bliss MR, Yamamoto F, Bobkov AA, Kiselar J, Liu Y, Cadwell GW, Khare S, Yu J, Barquilla A, Chung TD, Mustelin T, Schenk S, Bankston LA, Liddington RC, Pinkerton AB, Bottini N. Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase. Nat Chem Biol. 2017 Mar 27. doi: 10.1038/nchembio.2344. PMID:28346406 doi:http://dx.doi.org/10.1038/nchembio.2344
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