5ZLF

CRYSTAL STRUCTURE OF OCTAPRENYL PYROPHOSPHATE SYNTHASE FROM ESCHERICHIA COLI WITH ligand BPH-629

5ZLF の概要

• エントリーDOI: 10.2210/pdb5zlf/pdb
• 分子名称: Octaprenyl diphosphate synthase, [2-(3-DIBENZOFURAN-4-YL-PHENYL)-1-HYDROXY-1-PHOSPHONO-ETHYL]-PHOSPHONIC ACID, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: prenyltransferase, site-directed mutagenesis, product chain length, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Escherichia coli K-12
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 141496.43

構造登録者

Han, X.,Liu, W.D.,Zheng, Y.Y.,Ko, T.P.,Chen, C.C.,Guo, R.T. (登録日: 2018-03-27, 公開日: 2019-03-27, 最終更新日: 2023-11-22)

主引用文献

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

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: 30730737
DOI: 10.1021/acs.jmedchem.8b01878

実験手法

X-RAY DIFFRACTION (2.845 Å)