7rue: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==DAHP synthase complexed with trifluoropyruvate semicarbazone== | ==DAHP synthase complexed with trifluoropyruvate semicarbazone== | ||
<StructureSection load='7rue' size='340' side='right'caption='[[7rue]]' scene=''> | <StructureSection load='7rue' size='340' side='right'caption='[[7rue]], [[Resolution|resolution]] 2.50Å' 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=7RUE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RUE FirstGlance]. <br> | <table><tr><td colspan='2'>[[7rue]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RUE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RUE 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=7rue FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rue OCA], [https://pdbe.org/7rue PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rue RCSB], [https://www.ebi.ac.uk/pdbsum/7rue PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rue ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7QH:(2E)-2-(2-carbamoylhydrazinylidene)-3,3,3-trifluoropropanoic+acid'>7QH</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/3-deoxy-7-phosphoheptulonate_synthase 3-deoxy-7-phosphoheptulonate synthase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.54 2.5.1.54] </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=7rue FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rue OCA], [https://pdbe.org/7rue PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rue RCSB], [https://www.ebi.ac.uk/pdbsum/7rue PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rue ProSAT]</span></td></tr> | |||
</table> | </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> | |||
</div> | |||
<div class="pdbe-citations 7rue" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: 3-deoxy-7-phosphoheptulonate synthase]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Berti | [[Category: Berti, P J]] | ||
[[Category: Brown C]] | [[Category: Brown, C]] | ||
[[Category: Grainger R]] | [[Category: Grainger, R]] | ||
[[Category: Heimhalt M]] | [[Category: Heimhalt, M]] | ||
[[Category: Junop | [[Category: Junop, M S]] | ||
[[Category: Mukherjee P]] | [[Category: Mukherjee, P]] | ||
[[Category: Szabla R]] | [[Category: Szabla, R]] | ||
[[Category: Turner R]] | [[Category: Turner, R]] | ||
[[Category: Dahp synthase]] | |||
[[Category: Inhibitor complex]] | |||
[[Category: Lyase]] | |||
[[Category: Transferase-transferase inhibitor complex]] | |||