4h4b: Difference between revisions
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The entry | ==Human cytosolic 5'-nucleotidase II in complex with Anthraquinone-2,6- disulfonic acid== | ||
<StructureSection load='4h4b' size='340' side='right'caption='[[4h4b]], [[Resolution|resolution]] 2.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4h4b]] 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=4H4B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4H4B FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=11H:9,10-DIOXO-9,10-DIHYDROANTHRACENE-2,6-DISULFONIC+ACID'>11H</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4h4b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h4b OCA], [https://pdbe.org/4h4b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4h4b RCSB], [https://www.ebi.ac.uk/pdbsum/4h4b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4h4b ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/5NTC_HUMAN 5NTC_HUMAN] Autosomal recessive spastic paraplegia type 45. The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:24482476</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/5NTC_HUMAN 5NTC_HUMAN] May have a critical role in the maintenance of a constant composition of intracellular purine/pyrimidine nucleotides in cooperation with other nucleotidases. Preferentially hydrolyzes inosine 5'-monophosphate (IMP) and other purine nucleotides. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Clinical and preclinical observations have lead to the hypothesis that 5'-nucleotidase cN-II could constitute a therapeutic target in oncology, either per se or to increase the activity of cytotoxic nucleoside analogs. To identify potential cN-II inhibitors, we performed in silico screening of freely available chemical databases, in vitro enzymatic assays with recombinant cN-II, soaking experiments with crystals of truncated cN-II as well as biological evaluation of selected compounds, alone or in combination with cytotoxic nucleoside analogs, on cancer cells. The top ranked compounds from virtual screening included an anthraquinone derivative (AdiS) that were shown to block the enzyme activity with a K(i) of 2.0mM. Soaking experiments performed with crystals of truncated cN-II allowed to obtain crystallographic data at a resolution of 2.9A and indicating interaction between AdiS and F354/I152 situated in the effector site 1 of cN-II. In addition, this compound exhibited different levels of cytotoxicity in vitro on several cancer cell lines and increased the induction of apoptosis in RL cells incubated with 0.5 or 1.5muM cladribine, 0.05muM clofarabine or 30muM fludarabine. Finally, AdiS showed synergy with cladribine and additivity with clofarabine. This study showed that virtual screening is a useful tool for the identification of potent cN-II inhibitors, and our biological results indicated interesting activity for one lead compound that can be further developed as therapeutics. | |||
Identification and characterization of inhibitors of cytoplasmic 5'-nucleotidase cN-II issued from virtual screening.,Jordheim LP, Marton Z, Rhimi M, Cros-Perrial E, Lionne C, Peyrottes S, Dumontet C, Aghajari N, Chaloin L Biochem Pharmacol. 2012 Dec 7. pii: S0006-2952(12)00765-4. doi:, 10.1016/j.bcp.2012.11.024. PMID:23220537<ref>PMID:23220537</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4h4b" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Aghajari N]] | |||
[[Category: Rhimi M]] | |||