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{{STRUCTURE_4jhz|  PDB=4jhz  |  SCENE=  }}
==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==
===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=''>
{{ABSTRACT_PUBMED_23690068}}
== Structural highlights ==
<table><tr><td colspan='2'>[[4jhz]] is a 2 chain structure with sequence from [http://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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JHZ FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1KV:2-[4-(1,3-BENZODIOXOL-5-YLMETHYL)PIPERAZIN-1-YL]-N-[(1S,2S,5S)-2,5-DIMETHOXYCYCLOHEXYL]ACETAMIDE'>1KV</scene></td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3lpf|3lpf]], [[3k46|3k46]], [[3k4a|3k4a]], [[3k4d|3k4d]], [[3lpg|3lpg]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">b1617, gurA, gusA, JW1609, uidA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83333 Escherichia coli K-12])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Beta-glucuronidase Beta-glucuronidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.31 3.2.1.31] </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=4jhz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jhz OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4jhz RCSB], [http://www.ebi.ac.uk/pdbsum/4jhz PDBsum]</span></td></tr>
</table>
<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.


==About this Structure==
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>
[[4jhz]] is a 2 chain structure with sequence from [http://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].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
<ref group="xtra">PMID:023690068</ref><references group="xtra"/><references/>
</div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Beta-glucuronidase]]
[[Category: Beta-glucuronidase]]
[[Category: Escherichia coli k-12]]
[[Category: Escherichia coli k-12]]
[[Category: Redinbo, M R.]]
[[Category: Redinbo, M R]]
[[Category: Roberts, A B.]]
[[Category: Roberts, A B]]
[[Category: Wallace, B D.]]
[[Category: Wallace, B D]]
[[Category: Alpha/beta barrel]]
[[Category: Alpha/beta barrel]]
[[Category: Beta-sandwich domain]]
[[Category: Beta-sandwich domain]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Sugar-binding domain]]
[[Category: Sugar-binding domain]]
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