7RUD
DAHP synthase complex with trifluoropyruvate oxime
Summary for 7RUD
| Entry DOI | 10.2210/pdb7rud/pdb |
| Descriptor | Phospho-2-dehydro-3-deoxyheptonate aldolase, Phe-sensitive, (2Z)-3,3,3-trifluoro-2-(hydroxyimino)propanoic acid (3 entities in total) |
| Functional Keywords | dahp synthase, inhibitor, complex, lyase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Escherichia coli (strain K12) |
| Total number of polymer chains | 4 |
| Total formula weight | 152937.36 |
| Authors | Heimhalt, M.,Mukherjee, P.,Grainger, R.,Szabla, R.,Brown, C.,Turner, R.,Junop, M.S.,Berti, P.J. (deposition date: 2021-08-16, release date: 2021-11-17, Last modification date: 2023-10-18) |
| Primary citation | Heimhalt, M.,Mukherjee, P.,Grainger, R.A.,Szabla, R.,Brown, C.,Turner, R.,Junop, M.S.,Berti, P.J. An Inhibitor-in-Pieces Approach to DAHP Synthase Inhibition: Potent Enzyme and Bacterial Growth Inhibition. Acs Infect Dis., 7:3292-3302, 2021 Cited by PubMed Abstract: 3-Deoxy-d-heptulosonate-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, = 10 ± 1 nM. Three trifluoropyruvate (TFP)-based inhibitor fragments were efficient inhibitors with ligand efficiencies of up to 0.7 kcal mol/atom compared with 0.2 kcal mol/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 growth in culture with IC = 0.21 ± 0.01 and 0.77 ± 0.08 mg mL, 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. PubMed: 34761906DOI: 10.1021/acsinfecdis.1c00462 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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