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4q6r

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Current revision

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

Structural highlights

4q6r is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.4Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SGPL1_HUMAN Cleaves phosphorylated sphingoid bases (PSBs), such as sphingosine-1-phosphate, into fatty aldehydes and phosphoethanolamine. Elevates stress-induced ceramide production and apoptosis.^[1]

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Reiss U, Oskouian B, Zhou J, Gupta V, Sooriyakumaran P, Kelly S, Wang E, Merrill AH Jr, Saba JD. Sphingosine-phosphate lyase enhances stress-induced ceramide generation and apoptosis. J Biol Chem. 2004 Jan 9;279(2):1281-90. Epub 2003 Oct 21. PMID:14570870 doi:http://dx.doi.org/10.1074/jbc.M309646200
↑ Weiler S, Braendlin N, Beerli C, Bergsdorf C, Schubart A, Srinivas H, Oberhauser B, Billich A. 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. J Med Chem. 2014 May 8. PMID:24809814 doi:http://dx.doi.org/10.1021/jm500338n

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4q6r"

Categories: Homo sapiens | Large Structures | Srinivas H

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4q6r]] is a 2 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=4Q6R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Q6R FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=LLP:(2S)-2-AMINO-6-[[3-HYDROXY-2-METHYL-5-(PHOSPHONOOXYMETHYL)PYRIDIN-4-YL]METHYLIDENEAMINO]HEXANOIC+ACID'>LLP</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SIN:SUCCINIC+ACID'>SIN</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]] 2.4&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=LLP:(2S)-2-AMINO-6-[[3-HYDROXY-2-METHYL-5-(PHOSPHONOOXYMETHYL)PYRIDIN-4-YL]METHYLIDENEAMINO]HEXANOIC+ACID'>LLP</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SIN:SUCCINIC+ACID'>SIN</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=4q6r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4q6r OCA], [https://pdbe.org/4q6r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4q6r RCSB], [https://www.ebi.ac.uk/pdbsum/4q6r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4q6r ProSAT]</span></td></tr>
 </table>

4q6r

From Proteopedia

Current revision

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

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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