View source for 7zeg


==Human cytosolic 5' nucleotidase IIIB in complex with 3,4-diF-Bn7GMP==
<StructureSection load='7zeg' size='340' side='right'caption='[[7zeg]], [[Resolution|resolution]] 1.56&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7zeg]] 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=7ZEG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZEG 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]] 1.56&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IOO:N7-(3,4-difluorobenzyl)+guanosine+5-monophosphate'>IOO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=7zeg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zeg OCA], [https://pdbe.org/7zeg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zeg RCSB], [https://www.ebi.ac.uk/pdbsum/7zeg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zeg ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/5NT3B_HUMAN 5NT3B_HUMAN] Specifically hydrolyzes 7-methylguanosine monophosphate (m(7)GMP) to 7-methylguanosine and inorganic phosphate (PubMed:23223233, PubMed:24603684). The specific activity for m(7)GMP may protect cells against undesired salvage of m(7)GMP and its incorporation into nucleic acids (PubMed:23223233). Also has weak activity for CMP (PubMed:23223233, PubMed:24603684). UMP and purine nucleotides are poor substrates (PubMed:23223233).<ref>PMID:23223233</ref> <ref>PMID:24603684</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Cytosolic nucleotidases (cNs) catalyze dephosphorylation of nucleoside 5'-monophosphates and thereby contribute to the regulation of nucleotide levels in cells. cNs have also been shown to dephosphorylate several therapeutically relevant nucleotide analogues. cN-IIIB has shown in vitro a distinctive activity towards 7-mehtylguanosine monophosphate (m(7)GMP), which is one key metabolites of mRNA cap. Consequently, it has been proposed that cN-IIIB participates in mRNA cap turnover and prevents undesired accumulation and salvage of m(7)GMP. Here, we sought to develop molecular tools enabling more advanced studies on the cellular role of cN-IIIB. To that end, we performed substrate and inhibitor property profiling using a library of 41 substrate analogs. The most potent hit compounds (identified among m(7)GMP analogs) were used as a starting point for structure-activity relationship studies. As a result, we identified several 7-benzylguanosine 5'-monophosphate (Bn(7)GMP) derivatives as potent, unhydrolyzable cN-IIIB inhibitors. The mechanism of inhibition was elucidated using X-ray crystallography and molecular docking. Finally, we showed that compounds that potently inhibit recombinant cN-IIIB have the ability to inhibit m(7)GMP decay in cell lysates.

Substrate-Based Design of Cytosolic Nucleotidase IIIB Inhibitors and Structural Insights into Inhibition Mechanism.,Kubacka D, Kozarski M, Baranowski MR, Wojcik R, Panecka-Hofman J, Strzelecka D, Basquin J, Jemielity J, Kowalska J Pharmaceuticals (Basel). 2022 Apr 29;15(5). pii: ph15050554. doi:, 10.3390/ph15050554. PMID:35631380<ref>PMID:35631380</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7zeg" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Baranowski MR]]
[[Category: Basquin J]]
[[Category: Jemielity J]]
[[Category: Kowalska J]]
[[Category: Kozarski M]]
[[Category: Kubacka D]]
[[Category: Wojcik R]]