4q6r
From Proteopedia
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| - | ''' | + | ==Crystal structure of human sphingosine-1-phosphate lyase in complex with inhibitor 6-[(2R)-4-(4-benzyl-7-chlorophthalazin-1-yl)-2-methylpiperazin-1-yl]pyridine-3-carbonitrile== |
| + | <StructureSection load='4q6r' size='340' side='right' caption='[[4q6r]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4q6r]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Q6R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Q6R FirstGlance]. <br> | ||
| + | </td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=30J:6-[(2R)-4-(4-BENZYL-7-CHLOROPHTHALAZIN-1-YL)-2-METHYLPIPERAZIN-1-YL]PYRIDINE-3-CARBONITRILE'>30J</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SIN:SUCCINIC+ACID'>SIN</scene><br> | ||
| + | <tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=LLP:2-LYSINE(3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YLMETHANE)'>LLP</scene></td></tr> | ||
| + | <tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1hbx|1hbx]], [[3mc6|3mc6]]</td></tr> | ||
| + | <tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Sphinganine-1-phosphate_aldolase Sphinganine-1-phosphate aldolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.2.27 4.1.2.27] </span></td></tr> | ||
| + | <tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4q6r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4q6r OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4q6r RCSB], [http://www.ebi.ac.uk/pdbsum/4q6r PDBsum]</span></td></tr> | ||
| + | <table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Sphingosine-1-phosphate (S1P) lyase has recently been implicated as a therapeutic target for the treatment of multiple sclerosis (MS), based on studies in a genetic mouse model. Potent active-site directed inhibitors of the enzyme are not known so far. Here we describe the discovery of (4-benzyl-phthalazin-1-yl)-2-methyl-piperazin-1-yl]-nicotinonitrile 5 in a high-throughput screen using a biochemical assay, and its further optimization. This class of compounds was found to inhibit catalytic activity of S1PL by binding to the active site of the enzyme, as seen in the co-crystal structure of derivative 31 with the homodimeric human S1P lyase. 31 induces profound reduction of peripheral T cell numbers after oral dosage and confers pronounced protection in a rat model of multiple sclerosis. In conclusion, this novel class of direct S1P lyase inhibitors provides excellent tools to further explore the therapeutic potential of T cell-targeted therapies in multiple sclerosis and other autoimmune and inflammatory diseases. | ||
| - | + | Orally Active 7-Substituted (4-Benzyl-phthalazin-1-yl)-2-methyl-piperazin-1-yl]-nicotinonitriles as Active-site Inhibitors of Sphingosine-1-Phosphate Lyase for the Treatment of Multiple Sclerosis.,Weiler S, Braendlin N, Beerli C, Bergsdorf C, Schubart A, Srinivas H, Oberhauser B, Billich A J Med Chem. 2014 May 8. PMID:24809814<ref>PMID:24809814</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Sphinganine-1-phosphate aldolase]] | ||
| + | [[Category: Srinivas, H.]] | ||
| + | [[Category: Lyase-lyase inhibitor complex]] | ||
| + | [[Category: Plp]] | ||
| + | [[Category: Pyridoxal 5-phosphate-dependent enzyme]] | ||
Revision as of 09:09, 21 May 2014
Crystal structure of human sphingosine-1-phosphate lyase in complex with inhibitor 6-[(2R)-4-(4-benzyl-7-chlorophthalazin-1-yl)-2-methylpiperazin-1-yl]pyridine-3-carbonitrile
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