View source for 8g6c


==GTP Cyclohydrolase-IB with manganese==
<StructureSection load='8g6c' size='340' side='right'caption='[[8g6c]], [[Resolution|resolution]] 2.82&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8g6c]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Burkholderia_pseudomallei Burkholderia pseudomallei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8G6C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8G6C 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]] 2.82&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SNC:S-NITROSO-CYSTEINE'>SNC</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=8g6c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8g6c OCA], [https://pdbe.org/8g6c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8g6c RCSB], [https://www.ebi.ac.uk/pdbsum/8g6c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8g6c ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/GCH4_BURPS GCH4_BURPS] Converts GTP to 7,8-dihydroneopterin triphosphate.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Burkholderia thailandensis has emerged as a nonpathogenic surrogate for Burkholderia pseudomallei, the causative agent of melioidosis, and an important Gram-negative model bacterium for studying the biosynthesis and regulation of secondary metabolism. We recently reported that subinhibitory concentrations of trimethoprim induce vast changes in both the primary and secondary metabolome of B. thailandensis. In the current work, we show that the folate biosynthetic enzyme FolE2 is permissive under standard growth conditions but essential for B. thailandensis in the presence of subinhibitory doses of trimethoprim. Reasoning that FolE2 may serve as an attractive drug target, we screened for and identified ten inhibitors, including dehydrocostus lactone (DHL), parthenolide, and beta-lapachone, all of which are innocuous individually but form a chemical-synthetic lethal combination with subinhibitory doses of trimethoprim. We show that DHL is a mechanism-based inhibitor of FolE2 and capture the structure of the covalently inhibited enzyme using X-ray crystallography. In vitro, the combination of subinhibitory trimethoprim and DHL is more potent than Bactrim, the current standard of care against melioidosis. Moreover, unlike Bactrim, this combination does not affect the growth of most commensal and beneficial gut bacteria tested, thereby providing a degree of specificity against B. pseudomallei. Our work provides a path for identifying antimicrobial drug targets and for utilizing binary combinations of molecules that form a toxic cocktail based on metabolic idiosyncrasies of specific pathogens.

Combatting melioidosis with chemical synthetic lethality.,Zhang Y, McWhorter KL, Rosen PC, Klaus JR, Gallant E, Amaya Lopez CY, Jhunjhunwala R, Chandler JR, Davis KM, Seyedsayamdost MR Proc Natl Acad Sci U S A. 2024 Nov 12;121(46):e2406771121. doi: , 10.1073/pnas.2406771121. Epub 2024 Nov 4. PMID:39495920<ref>PMID:39495920</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8g6c" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Burkholderia pseudomallei]]
[[Category: Large Structures]]
[[Category: Amaya Lopez CY]]
[[Category: Davis KM]]
[[Category: McWhorter KL]]