7mdc: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7mdc]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MDC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MDC FirstGlance]. <br> | <table><tr><td colspan='2'>[[7mdc]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MDC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MDC FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2PE:NONAETHYLENE+GLYCOL'>2PE</scene>, <scene name='pdbligand=97N:(2S)-2,3-DIHYDROXYPROPYL+(9Z)-HEXADEC-9-ENOATE'>97N</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=YX7:[( | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2PE:NONAETHYLENE+GLYCOL'>2PE</scene>, <scene name='pdbligand=97N:(2S)-2,3-DIHYDROXYPROPYL+(9Z)-HEXADEC-9-ENOATE'>97N</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=YX7:[(1~{S})-3-azanyl-1-(hexanoylamino)-3-oxidanylidene-propyl]boronic+acid'>YX7</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=7mdc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mdc OCA], [https://pdbe.org/7mdc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mdc RCSB], [https://www.ebi.ac.uk/pdbsum/7mdc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mdc ProSAT]</span></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=7mdc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mdc OCA], [https://pdbe.org/7mdc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mdc RCSB], [https://www.ebi.ac.uk/pdbsum/7mdc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mdc ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/Q0P7K6_ECOLX Q0P7K6_ECOLX] | [https://www.uniprot.org/uniprot/Q0P7K6_ECOLX Q0P7K6_ECOLX] | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The human gut bacterial genotoxin colibactin is a possible key driver of colorectal cancer (CRC) development. Understanding colibactin's biological effects remains difficult owing to the instability of the proposed active species and the complexity of the gut microbiota. Here, we report small molecule boronic acid inhibitors of colibactin biosynthesis. Designed to mimic the biosynthetic precursor precolibactin, these compounds potently inhibit the colibactin-activating peptidase ClbP. Using biochemical assays and crystallography, we show that they engage the ClbP binding pocket, forming a covalent bond with the catalytic serine. These inhibitors reproduce the phenotypes observed in a clbP deletion mutant and block the genotoxic effects of colibactin on eukaryotic cells. The availability of ClbP inhibitors will allow precise, temporal control over colibactin production, enabling further study of its contributions to CRC. Finally, application of our inhibitors to related peptidase-encoding pathways highlights the power of chemical tools to probe natural product biosynthesis. | |||
A small molecule inhibitor prevents gut bacterial genotoxin production.,Volpe MR, Velilla JA, Daniel-Ivad M, Yao JJ, Stornetta A, Villalta PW, Huang HC, Bachovchin DA, Balbo S, Gaudet R, Balskus EP Nat Chem Biol. 2023 Feb;19(2):159-167. doi: 10.1038/s41589-022-01147-8. Epub 2022 , Oct 17. PMID:36253549<ref>PMID:36253549</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7mdc" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | *[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Latest revision as of 11:58, 17 October 2024
Full-length wildtype ClbP inhibited by hexanoyl-D-asparagine boronic acidFull-length wildtype ClbP inhibited by hexanoyl-D-asparagine boronic acid
Structural highlights
FunctionPublication Abstract from PubMedThe human gut bacterial genotoxin colibactin is a possible key driver of colorectal cancer (CRC) development. Understanding colibactin's biological effects remains difficult owing to the instability of the proposed active species and the complexity of the gut microbiota. Here, we report small molecule boronic acid inhibitors of colibactin biosynthesis. Designed to mimic the biosynthetic precursor precolibactin, these compounds potently inhibit the colibactin-activating peptidase ClbP. Using biochemical assays and crystallography, we show that they engage the ClbP binding pocket, forming a covalent bond with the catalytic serine. These inhibitors reproduce the phenotypes observed in a clbP deletion mutant and block the genotoxic effects of colibactin on eukaryotic cells. The availability of ClbP inhibitors will allow precise, temporal control over colibactin production, enabling further study of its contributions to CRC. Finally, application of our inhibitors to related peptidase-encoding pathways highlights the power of chemical tools to probe natural product biosynthesis. A small molecule inhibitor prevents gut bacterial genotoxin production.,Volpe MR, Velilla JA, Daniel-Ivad M, Yao JJ, Stornetta A, Villalta PW, Huang HC, Bachovchin DA, Balbo S, Gaudet R, Balskus EP Nat Chem Biol. 2023 Feb;19(2):159-167. doi: 10.1038/s41589-022-01147-8. Epub 2022 , Oct 17. PMID:36253549[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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