View source for 4jhz


==Structure of E. coli beta-Glucuronidase bound with a novel, potent inhibitor 2-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-N-[(1S,2S,5S)-2,5-dimethoxycyclohexyl]acetamide==
<StructureSection load='4jhz' size='340' side='right'caption='[[4jhz]], [[Resolution|resolution]] 2.83&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4jhz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JHZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JHZ 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]] 2.831&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1KV:2-[4-(1,3-BENZODIOXOL-5-YLMETHYL)PIPERAZIN-1-YL]-N-[(1S,2S,5S)-2,5-DIMETHOXYCYCLOHEXYL]ACETAMIDE'>1KV</scene>, <scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</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=4jhz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jhz OCA], [https://pdbe.org/4jhz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jhz RCSB], [https://www.ebi.ac.uk/pdbsum/4jhz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jhz ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/BGLR_ECOLI BGLR_ECOLI] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Bacterial beta-glucuronidases expressed by the symbiotic intestinal microbiota appear to play important roles in drug-induced epithelial cell toxicity in the gastrointestinal (GI) tract. For the anticancer drug CPT-11 (irinotecan) and the nonsteroidal anti-inflammatory drug diclofenac, it has been shown that removal of the glucuronide moieties from drug metabolites by bacterial beta-glucuronidases in the GI lumen can significantly damage the intestinal epithelium. Furthermore, selective disruption of bacterial beta-glucuronidases by small molecule inhibitors alleviates these side effects, which, for CPT-11 {7-ethyl-10-[4-(1-piperidino)-1-piperidino]}, can be dose limiting. Here we characterize novel microbial beta-glucuronidase inhibitors that inhibit Escherichia coli beta-glucuronidase in vitro with Ki values between 180 nM and 2 muM, and disrupt the enzyme in E. coli cells, with EC50 values as low as 300 nM. All compounds are selective for E. coli beta-glucuronidase without inhibiting purified mammalian beta-glucuronidase, and they do not impact the survival of either bacterial or mammalian cells. The 2.8 A resolution crystal structure of one inhibitor bound to E. coli beta-glucuronidase demonstrates that it contacts and orders only a portion of the "bacterial loop" present in microbial, but not mammalian, beta-glucuronidases. The most potent compound examined in this group was found to protect mice against CPT-11-induced diarrhea. Taken together, these data advance our understanding of the chemical and structural basis of selective microbial beta-glucuronidase inhibition, which may improve human drug efficacy and toxicity.

Molecular Insights into Microbial beta-Glucuronidase Inhibition to Abrogate CPT-11 Toxicity.,Roberts AB, Wallace BD, Venkatesh MK, Mani S, Redinbo MR Mol Pharmacol. 2013 Aug;84(2):208-17. doi: 10.1124/mol.113.085852. Epub 2013 May , 20. PMID:23690068<ref>PMID:23690068</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4jhz" style="background-color:#fffaf0;"></div>

==See Also==
*[[Glucuronisidase 3D structures|Glucuronisidase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli K-12]]
[[Category: Large Structures]]
[[Category: Redinbo MR]]
[[Category: Roberts AB]]
[[Category: Wallace BD]]