5ZHE
STRUCTURE OF E. COLI UNDECAPRENYL DIPHOSPHATE SYNTHASE IN COMPLEX WITH BPH-981
Summary for 5ZHE
| Entry DOI | 10.2210/pdb5zhe/pdb |
| Descriptor | Ditrans,polycis-undecaprenyl-diphosphate synthase ((2E,6E)-farnesyl-diphosphate specific), 2-hydroxy-6-(tetradecyloxy)benzoic acid (3 entities in total) |
| Functional Keywords | metal-binding, substrate binding, acidocalcisomal pyrophosphatase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Escherichia coli K-12 |
| Total number of polymer chains | 2 |
| Total formula weight | 57312.75 |
| Authors | Gao, J.,Liu, W.D.,Zheng, Y.Y.,Ko, T.P.,Chen, C.C.,Guo, R.T. (deposition date: 2018-03-13, release date: 2019-03-13, Last modification date: 2023-11-22) |
| Primary citation | Malwal, S.R.,Chen, L.,Hicks, H.,Qu, F.,Liu, W.,Shillo, A.,Law, W.X.,Zhang, J.,Chandnani, N.,Han, X.,Zheng, Y.,Chen, C.C.,Guo, R.T.,AbdelKhalek, A.,Seleem, M.N.,Oldfield, E. Discovery of Lipophilic Bisphosphonates That Target Bacterial Cell Wall and Quinone Biosynthesis. J.Med.Chem., 62:2564-2581, 2019 Cited by PubMed Abstract: We report that alkyl-substituted bisphosphonates have activity against Bacillus anthracis Sterne (0.40 μg/mL), Mycobacterium smegmatis (1.4 μg/mL), Bacillus subtilis (1.0 μg/mL), and Staphylococcus aureus (13 μg/mL). In many cases, there is no effect of serum binding, as well as low activity against a human embryonic kidney cell line. Targeting of isoprenoid biosynthesis is involved with 74 having IC values of ∼100 nM against heptaprenyl diphosphate synthase and 200 nM against farnesyl diphosphate synthase. B. subtilis growth inhibition was rescued by addition of farnesyl diphosphate, menaquinone-4 (MK-4), or undecaprenyl phosphate (UP), and the combination of MK-4 and UP resulted in a 25× increase in ED, indicating targeting of both quinone and cell wall biosynthesis. Clostridioides difficile was inhibited by 74, and since this organism does not synthesize quinones, cell wall biosynthesis is the likely target. We also solved three X-ray structures of inhibitors bound to octaprenyl diphosphate and/or undecaprenyl diphosphate synthases. PubMed: 30730737DOI: 10.1021/acs.jmedchem.8b01878 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.18 Å) |
Structure validation
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