7rud: Difference between revisions
New page: '''Unreleased structure''' The entry 7rud is ON HOLD Authors: Description: Category: Unreleased Structures |
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==DAHP synthase complex with trifluoropyruvate oxime== | |||
<StructureSection load='7rud' size='340' side='right'caption='[[7rud]], [[Resolution|resolution]] 2.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7rud]] is a 4 chain structure with sequence from [https://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=7RUD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RUD 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]] 2.8Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7QE:(2Z)-3,3,3-trifluoro-2-(hydroxyimino)propanoic+acid'>7QE</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=7rud FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rud OCA], [https://pdbe.org/7rud PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rud RCSB], [https://www.ebi.ac.uk/pdbsum/7rud PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rud ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/AROG_ECOLI AROG_ECOLI] Stereospecific condensation of phosphoenolpyruvate (PEP) and D-erythrose-4-phosphate (E4P) giving rise to 3-deoxy-D-arabino-heptulosonate-7-phosphate (DAHP). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
3-Deoxy-d-arabinoheptulosonate-7-phosphate (DAHP) synthase catalyzes the first step in the shikimate biosynthetic pathway and is an antimicrobial target. We used an inhibitor-in-pieces approach, based on the previously reported inhibitor DAHP oxime, to screen inhibitor fragments in the presence and absence of glycerol 3-phosphate to occupy the distal end of the active site. This led to DAHP hydrazone, the most potent inhibitor to date, Ki = 10 +/- 1 nM. Three trifluoropyruvate (TFP)-based inhibitor fragments were efficient inhibitors with ligand efficiencies of up to 0.7 kcal mol(-1)/atom compared with 0.2 kcal mol(-1)/atom for a typical good inhibitor. The crystal structures showed the TFP-based inhibitors binding upside down in the active site relative to DAHP oxime, providing new avenues for inhibitor development. The ethyl esters of TFP oxime and TFP semicarbazone prevented E. coli growth in culture with IC50 = 0.21 +/- 0.01 and 0.77 +/- 0.08 mg mL(-1), respectively. Overexpressing DAHP synthase relieved growth inhibition, demonstrating that DAHP synthase was the target. Growth inhibition occurred in media containing aromatic amino acids, suggesting that growth inhibition was due to depletion of some other product(s) of the shikimate pathway, possibly folate. | |||
An Inhibitor-in-Pieces Approach to DAHP Synthase Inhibition: Potent Enzyme and Bacterial Growth Inhibition.,Heimhalt M, Mukherjee P, Grainger RA, Szabla R, Brown C, Turner R, Junop MS, Berti PJ ACS Infect Dis. 2021 Nov 11. doi: 10.1021/acsinfecdis.1c00462. PMID:34761906<ref>PMID:34761906</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7rud" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[DAHP synthase 3D structures|DAHP synthase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Escherichia coli K-12]] | |||
[[Category: Large Structures]] | |||
[[Category: Berti PJ]] | |||
[[Category: Brown C]] | |||
[[Category: Grainger R]] | |||
[[Category: Heimhalt M]] | |||
[[Category: Junop MS]] | |||
[[Category: Mukherjee P]] | |||
[[Category: Szabla R]] | |||
[[Category: Turner R]] | |||
Latest revision as of 19:39, 18 October 2023
DAHP synthase complex with trifluoropyruvate oximeDAHP synthase complex with trifluoropyruvate oxime
Structural highlights
FunctionAROG_ECOLI Stereospecific condensation of phosphoenolpyruvate (PEP) and D-erythrose-4-phosphate (E4P) giving rise to 3-deoxy-D-arabino-heptulosonate-7-phosphate (DAHP). Publication Abstract from PubMed3-Deoxy-d-arabinoheptulosonate-7-phosphate (DAHP) synthase catalyzes the first step in the shikimate biosynthetic pathway and is an antimicrobial target. We used an inhibitor-in-pieces approach, based on the previously reported inhibitor DAHP oxime, to screen inhibitor fragments in the presence and absence of glycerol 3-phosphate to occupy the distal end of the active site. This led to DAHP hydrazone, the most potent inhibitor to date, Ki = 10 +/- 1 nM. Three trifluoropyruvate (TFP)-based inhibitor fragments were efficient inhibitors with ligand efficiencies of up to 0.7 kcal mol(-1)/atom compared with 0.2 kcal mol(-1)/atom for a typical good inhibitor. The crystal structures showed the TFP-based inhibitors binding upside down in the active site relative to DAHP oxime, providing new avenues for inhibitor development. The ethyl esters of TFP oxime and TFP semicarbazone prevented E. coli growth in culture with IC50 = 0.21 +/- 0.01 and 0.77 +/- 0.08 mg mL(-1), respectively. Overexpressing DAHP synthase relieved growth inhibition, demonstrating that DAHP synthase was the target. Growth inhibition occurred in media containing aromatic amino acids, suggesting that growth inhibition was due to depletion of some other product(s) of the shikimate pathway, possibly folate. An Inhibitor-in-Pieces Approach to DAHP Synthase Inhibition: Potent Enzyme and Bacterial Growth Inhibition.,Heimhalt M, Mukherjee P, Grainger RA, Szabla R, Brown C, Turner R, Junop MS, Berti PJ ACS Infect Dis. 2021 Nov 11. doi: 10.1021/acsinfecdis.1c00462. PMID:34761906[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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