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==Human cytosolic 5'-nucleotidase II soaked with 10mM 7-Benzyloxymethyl-7H-adenine== | ==Human cytosolic 5'-nucleotidase II soaked with 10mM 7-Benzyloxymethyl-7H-adenine== | ||
<StructureSection load='6fis' size='340' side='right' caption='[[6fis]], [[Resolution|resolution]] 2.30Å' scene=''> | <StructureSection load='6fis' size='340' side='right' caption='[[6fis]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6fis]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FIS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FIS FirstGlance]. <br> | <table><tr><td colspan='2'>[[6fis]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FIS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FIS FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4h4b|4h4b]], [[6fir|6fir]], [[5cqz|5cqz]], [[5cr7|5cr7]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4h4b|4h4b]], [[6fir|6fir]], [[5cqz|5cqz]], [[5cr7|5cr7]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NT5C2, NT5B, NT5CP, PNT5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/5'-nucleotidase 5'-nucleotidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.5 3.1.3.5] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/5'-nucleotidase 5'-nucleotidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.5 3.1.3.5] </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=6fis FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fis OCA], [http://pdbe.org/6fis PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fis RCSB], [http://www.ebi.ac.uk/pdbsum/6fis PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fis ProSAT]</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=6fis FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fis OCA], [http://pdbe.org/6fis PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fis RCSB], [http://www.ebi.ac.uk/pdbsum/6fis PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fis ProSAT]</span></td></tr> | ||
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== Function == | == Function == | ||
[[http://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. | [[http://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 == | |||
The development of cytosolic 5'-nucleotidase II (cN-II) inhibitors is essential to validate cN-II as a potential target for the reversion of resistance to cytotoxic nucleoside analogues. We previously reported a fragment-based approach combined with molecular modelling, herein, the selected hit-fragments were used again in another computational approach based on the Ilib-diverse (a software enabling to build virtual molecule libraries through fragment based de novo design) program to generate a focused library of potential inhibitors. A molecular scaffold related to a previously identified compound was selected and led to a novel series of compounds. Ten out of nineteen derivatives showed 50-75% inhibition on the purified recombinant protein at 200muM and among them three derivatives (12, 13 and 18) exhibited Ki in the sub-millimolar range (0.84, 2.4 and 0.58mM, respectively). Despite their only modest potency, the cN-II inhibitors showed synergistic effects when used in combination with cytotoxic purine nucleoside analogues on cancer cells. Therefore, these derivatives represent a family of non-nucleos(t)idic cN-II inhibitors with potential usefulness to overcome cancer drug resistance especially in hematological malignancies in which cN-II activity has been described as an important parameter. | |||
Lead optimization and biological evaluation of fragment-based cN-II inhibitors.,Guillon R, Rahimova R, Preeti, Egron D, Rouanet S, Dumontet C, Aghajari N, Jordheim LP, Chaloin L, Peyrottes S Eur J Med Chem. 2019 Feb 14;168:28-44. doi: 10.1016/j.ejmech.2019.02.040. PMID:30798051<ref>PMID:30798051</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6fis" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
| Line 18: | Line 28: | ||
</StructureSection> | </StructureSection> | ||
[[Category: 5'-nucleotidase]] | [[Category: 5'-nucleotidase]] | ||
[[Category: Human]] | |||
[[Category: Aghajari, N]] | [[Category: Aghajari, N]] | ||
[[Category: Preeti, P]] | [[Category: Preeti, P]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
Latest revision as of 11:22, 6 March 2019
Human cytosolic 5'-nucleotidase II soaked with 10mM 7-Benzyloxymethyl-7H-adenineHuman cytosolic 5'-nucleotidase II soaked with 10mM 7-Benzyloxymethyl-7H-adenine
Structural highlights
Disease[5NTC_HUMAN] Autosomal recessive spastic paraplegia type 45. The disease is caused by mutations affecting the gene represented in this entry.[1] Function[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. Publication Abstract from PubMedThe development of cytosolic 5'-nucleotidase II (cN-II) inhibitors is essential to validate cN-II as a potential target for the reversion of resistance to cytotoxic nucleoside analogues. We previously reported a fragment-based approach combined with molecular modelling, herein, the selected hit-fragments were used again in another computational approach based on the Ilib-diverse (a software enabling to build virtual molecule libraries through fragment based de novo design) program to generate a focused library of potential inhibitors. A molecular scaffold related to a previously identified compound was selected and led to a novel series of compounds. Ten out of nineteen derivatives showed 50-75% inhibition on the purified recombinant protein at 200muM and among them three derivatives (12, 13 and 18) exhibited Ki in the sub-millimolar range (0.84, 2.4 and 0.58mM, respectively). Despite their only modest potency, the cN-II inhibitors showed synergistic effects when used in combination with cytotoxic purine nucleoside analogues on cancer cells. Therefore, these derivatives represent a family of non-nucleos(t)idic cN-II inhibitors with potential usefulness to overcome cancer drug resistance especially in hematological malignancies in which cN-II activity has been described as an important parameter. Lead optimization and biological evaluation of fragment-based cN-II inhibitors.,Guillon R, Rahimova R, Preeti, Egron D, Rouanet S, Dumontet C, Aghajari N, Jordheim LP, Chaloin L, Peyrottes S Eur J Med Chem. 2019 Feb 14;168:28-44. doi: 10.1016/j.ejmech.2019.02.040. PMID:30798051[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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