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| | <StructureSection load='6xig' size='340' side='right'caption='[[6xig]], [[Resolution|resolution]] 1.59Å' scene=''> | | <StructureSection load='6xig' size='340' side='right'caption='[[6xig]], [[Resolution|resolution]] 1.59Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6xig]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Pedhd Pedhd]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XIG OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6XIG FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6xig]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Pedobacter_heparinus_DSM_2366 Pedobacter heparinus DSM 2366]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XIG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XIG FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SF4:IRON/SULFUR+CLUSTER'>SF4</scene>, <scene name='pdbligand=TAR:D(-)-TARTARIC+ACID'>TAR</scene></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]] 1.59Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mqnE, Phep_1880 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=485917 PEDHD])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SF4:IRON/SULFUR+CLUSTER'>SF4</scene>, <scene name='pdbligand=TAR:D(-)-TARTARIC+ACID'>TAR</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Aminodeoxyfutalosine_synthase Aminodeoxyfutalosine synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.120 2.5.1.120] </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=6xig FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xig OCA], [https://pdbe.org/6xig PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xig RCSB], [https://www.ebi.ac.uk/pdbsum/6xig PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xig ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6xig FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xig OCA], [http://pdbe.org/6xig PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6xig RCSB], [http://www.ebi.ac.uk/pdbsum/6xig PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6xig ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/C6XW09_PEDHD C6XW09_PEDHD]] Radical SAM enzyme that catalyzes the addition of the adenosyl radical to the double bond of 3-[(1-carboxyvinyl)oxy]benzoate, leading to aminodeoxyfutalosine (AFL), a key intermediate in the formation of menaquinone (MK, vitamin K2) from chorismate.[HAMAP-Rule:MF_00993] | + | [https://www.uniprot.org/uniprot/C6XW09_PEDHD C6XW09_PEDHD] Radical SAM enzyme that catalyzes the addition of the adenosyl radical to the double bond of 3-[(1-carboxyvinyl)oxy]benzoate, leading to aminodeoxyfutalosine (AFL), a key intermediate in the formation of menaquinone (MK, vitamin K2) from chorismate.[HAMAP-Rule:MF_00993] |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | Antibiotic resistance continues to spread at an alarming rate, outpacing the introduction of new therapeutics and threatening to globally undermine health care. There is a crucial need for new strategies that selectively target specific pathogens while leaving the majority of the microbiome untouched, thus averting the debilitating and sometimes fatal occurrences of opportunistic infections. To address these challenges, we have adopted a unique strategy that focuses on oxygen-sensitive proteins, an untapped set of therapeutic targets. MqnE is a member of the radical S-adenosyl-l-methionine (RS) superfamily, all of which rely on an oxygen-sensitive [4Fe-4S] cluster for catalytic activity. MqnE catalyzes the conversion of didehydrochorismate to aminofutalosine in the essential menaquinone biosynthetic pathway present in a limited set of species, including the gut pathogen Helicobacter pylori (Hp), making it an attractive target for narrow-spectrum antibiotic development. Indeed, we show that MqnE is inhibited by the mechanism-derived 2-fluoro analogue of didehydrochorismate (2F-DHC) due to accumulation of a radical intermediate under turnover conditions. Structures of MqnE in the apo and product-bound states afford insight into its catalytic mechanism, and electron paramagnetic resonance approaches provide direct spectroscopic evidence consistent with the predicted structure of the radical intermediate. In addition, we demonstrate the essentiality of the menaquinone biosynthetic pathway and unambiguously validate 2F-DHC as a selective inhibitor of Hp growth that exclusively targets MqnE. These data provide the foundation for designing effective Hp therapies and demonstrate proof of principle that radical SAM proteins can be effectively leveraged as therapeutic targets.
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| - | Narrow-Spectrum Antibiotic Targeting of the Radical SAM Enzyme MqnE in Menaquinone Biosynthesis.,Carl AG, Harris LD, Feng M, Nordstrom LU, Gerfen GJ, Evans GB, Silakov A, Almo SC, Grove TL Biochemistry. 2020 Jul 14;59(27):2562-2575. doi: 10.1021/acs.biochem.0c00070., Epub 2020 Jul 5. PMID:32627538<ref>PMID:32627538</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
| + | |
| - | <div class="pdbe-citations 6xig" style="background-color:#fffaf0;"></div>
| + | |
| - | == References ==
| + | |
| - | <references/>
| + | |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Aminodeoxyfutalosine synthase]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Pedhd]] | + | [[Category: Pedobacter heparinus DSM 2366]] |
| - | [[Category: Almo, S C]] | + | [[Category: Almo SC]] |
| - | [[Category: Bonanno, J B]] | + | [[Category: Bonanno JB]] |
| - | [[Category: Grove, T L]] | + | [[Category: Grove TL]] |
| - | [[Category: Biosynthetic protein]]
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| - | [[Category: Iron-sulfur cluster]]
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| - | [[Category: Menaquinone biosynthesis]]
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| - | [[Category: Radical sam]]
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