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==Structure of Bifidobacterium dentium beta-glucuronidase complexed with C6-propyl uronic isofagomine== | ==Structure of Bifidobacterium dentium beta-glucuronidase complexed with C6-propyl uronic isofagomine== | ||
<StructureSection load='6ldd' size='340' side='right'caption='[[6ldd]]' scene=''> | <StructureSection load='6ldd' size='340' side='right'caption='[[6ldd]], [[Resolution|resolution]] 2.21Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LDD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LDD FirstGlance]. <br> | <table><tr><td colspan='2'>[[6ldd]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Bifidobacterium_dentium_Bd1 Bifidobacterium dentium Bd1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LDD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LDD FirstGlance]. <br> | ||
</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=6ldd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ldd OCA], [https://pdbe.org/6ldd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ldd RCSB], [https://www.ebi.ac.uk/pdbsum/6ldd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ldd ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.205Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CKX:(2~{S},3~{S},4~{R},5~{R})-4,5-bis(oxidanyl)-2-propyl-piperidine-3-carboxylic+acid'>CKX</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=6ldd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ldd OCA], [https://pdbe.org/6ldd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ldd RCSB], [https://www.ebi.ac.uk/pdbsum/6ldd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ldd ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/D2Q7B1_BIFDB D2Q7B1_BIFDB] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Irinotecan inhibits cell proliferation and thus is used for the primary treatment of colorectal cancer. Metabolism of irinotecan involves incorporation of beta-glucuronic acid to facilitate excretion. During transit of the glucuronidated product through the gastrointestinal tract, an induced upregulation of gut microbial beta-glucuronidase (GUS) activity may cause severe diarrhea and thus force many patients to stop treatment. We herein report the development of uronic isofagomine (UIFG) derivatives that act as general, potent inhibitors of bacterial GUSs, especially those of Escherichia coli and Clostridium perfringens. The best inhibitor, C6-nonyl UIFG, is 23,300-fold more selective for E. coli GUS than for human GUS (Ki = 0.0045 and 105 muM, respectively). Structural evidence indicated that the loss of coordinated water molecules, with the consequent increase in entropy, contributes to the high affinity and selectivity for bacterial GUSs. The inhibitors also effectively reduced irinotecan-induced diarrhea in mice without damaging intestinal epithelial cells. | |||
Entropy-driven binding of gut bacterial beta-glucuronidase inhibitors ameliorates irinotecan-induced toxicity.,Lin HY, Chen CY, Lin TC, Yeh LF, Hsieh WC, Gao S, Burnouf PA, Chen BM, Hsieh TJ, Dashnyam P, Kuo YH, Tu Z, Roffler SR, Lin CH Commun Biol. 2021 Mar 4;4(1):280. doi: 10.1038/s42003-021-01815-w. PMID:33664385<ref>PMID:33664385</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6ldd" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Galactosidase 3D structures|Galactosidase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Bifidobacterium dentium Bd1]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Hsieh T-J]] | [[Category: Hsieh T-J]] | ||
[[Category: Lin C-H]] | [[Category: Lin C-H]] | ||
[[Category: Lin H-Y]] | [[Category: Lin H-Y]] | ||
Latest revision as of 13:57, 22 November 2023
Structure of Bifidobacterium dentium beta-glucuronidase complexed with C6-propyl uronic isofagomineStructure of Bifidobacterium dentium beta-glucuronidase complexed with C6-propyl uronic isofagomine
Structural highlights
FunctionPublication Abstract from PubMedIrinotecan inhibits cell proliferation and thus is used for the primary treatment of colorectal cancer. Metabolism of irinotecan involves incorporation of beta-glucuronic acid to facilitate excretion. During transit of the glucuronidated product through the gastrointestinal tract, an induced upregulation of gut microbial beta-glucuronidase (GUS) activity may cause severe diarrhea and thus force many patients to stop treatment. We herein report the development of uronic isofagomine (UIFG) derivatives that act as general, potent inhibitors of bacterial GUSs, especially those of Escherichia coli and Clostridium perfringens. The best inhibitor, C6-nonyl UIFG, is 23,300-fold more selective for E. coli GUS than for human GUS (Ki = 0.0045 and 105 muM, respectively). Structural evidence indicated that the loss of coordinated water molecules, with the consequent increase in entropy, contributes to the high affinity and selectivity for bacterial GUSs. The inhibitors also effectively reduced irinotecan-induced diarrhea in mice without damaging intestinal epithelial cells. Entropy-driven binding of gut bacterial beta-glucuronidase inhibitors ameliorates irinotecan-induced toxicity.,Lin HY, Chen CY, Lin TC, Yeh LF, Hsieh WC, Gao S, Burnouf PA, Chen BM, Hsieh TJ, Dashnyam P, Kuo YH, Tu Z, Roffler SR, Lin CH Commun Biol. 2021 Mar 4;4(1):280. doi: 10.1038/s42003-021-01815-w. PMID:33664385[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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