4l02: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4l02]] is a 3 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=4L02 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4L02 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4l02]] is a 3 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=4L02 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4L02 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1V2:(2R,4S)-1-[2-(4-{[4-(3,4-DICHLOROPHENYL)-1,3-THIAZOL-2-YL]AMINO}PHENYL)ETHYL]-2-(HYDROXYMETHYL)PIPERIDIN-4-OL'>1V2</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]] 2.75&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1V2:(2R,4S)-1-[2-(4-{[4-(3,4-DICHLOROPHENYL)-1,3-THIAZOL-2-YL]AMINO}PHENYL)ETHYL]-2-(HYDROXYMETHYL)PIPERIDIN-4-OL'>1V2</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=4l02 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l02 OCA], [https://pdbe.org/4l02 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4l02 RCSB], [https://www.ebi.ac.uk/pdbsum/4l02 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4l02 ProSAT]</span></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=4l02 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l02 OCA], [https://pdbe.org/4l02 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4l02 RCSB], [https://www.ebi.ac.uk/pdbsum/4l02 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4l02 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[https://www.uniprot.org/uniprot/SPHK1_HUMAN SPHK1_HUMAN] Catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions. Also acts on D-erythro-sphingosine and to a lesser extent sphinganine, but not other lipids, such as D,L-threo-dihydrosphingosine, N,N-dimethylsphingosine, diacylglycerol, ceramide, or phosphatidylinositol.<ref>PMID:20577214</ref>  
[https://www.uniprot.org/uniprot/SPHK1_HUMAN SPHK1_HUMAN] Catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions. Also acts on D-erythro-sphingosine and to a lesser extent sphinganine, but not other lipids, such as D,L-threo-dihydrosphingosine, N,N-dimethylsphingosine, diacylglycerol, ceramide, or phosphatidylinositol.<ref>PMID:20577214</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Sphingosine-1-phosphate (S1P) signaling plays a vital role in mitogenesis, cell migration and angiogenesis. Sphingosine kinases (SphKs) catalyze a key step in sphingomyelin metabolism that leads to the production of S1P. There are two isoforms of SphK and observations made with SphK deficient mice show the two isoforms can compensate for each other's loss. Thus, inhibition of both isoforms is likely required to block SphK dependent angiogenesis. A structure based approach was used to design and synthesize a series of SphK inhibitors resulting in the identification of the first potent inhibitors of both isoforms of human SphK. Additionally, to our knowledge, this series of inhibitors contains the only sufficiently potent inhibitors of murine SphK1 with suitable physico-chemical properties to pharmacologically interrogate the role of SphK1 in rodent models and to reproduce the phenotype of SphK1 (-/-) mice.


Structure guided design of a series of sphingosine kinase (SphK) inhibitors.,Gustin DJ, Li Y, Brown ML, Min X, Schmitt MJ, Wanska M, Wang X, Connors R, Johnstone S, Cardozo M, Cheng AC, Jeffries S, Franks B, Li S, Shen S, Wong M, Wesche H, Xu G, Carlson TJ, Plant M, Morgenstern K, Rex K, Schmitt J, Coxon A, Walker N, Kayser F, Wang Z Bioorg Med Chem Lett. 2013 Jun 20. pii: S0960-894X(13)00739-7. doi:, 10.1016/j.bmcl.2013.06.030. PMID:23845219<ref>PMID:23845219</ref>
==See Also==
 
*[[Sphingosine kinase|Sphingosine kinase]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4l02" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>

Latest revision as of 12:16, 1 March 2024

Crystal Structure of SphK1 with inhibitor

4l02, resolution 2.75Å

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