3TH8

Structure of E. coli undecaprenyl diphosphate synthase complexed with BPH-1063

Summary for 3TH8

• Entry DOI: 10.2210/pdb3th8/pdb
• Descriptor: Undecaprenyl pyrophosphate synthase, (2Z)-4-({3-[3-(hexyloxy)phenyl]propyl}amino)-2-hydroxy-4-oxobut-2-enoic acid (3 entities in total)
• Functional Keywords: all helices, prenyl transferase, farneyl diphosphate binding, isopentenyl diphosphate binding, prenylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 57311.68

Authors

Cao, R.,Zhu, W.,Zhang, Y.,Oldfield, E. (deposition date: 2011-08-18, release date: 2012-07-04, Last modification date: 2023-09-13)

Primary citation

Zhang, Y.,Lin, F.-Y.,Li, K.,Zhu, W.,Liu, Y.L.,Cao, R.,Pang, R.,Lee, E.,Axelson, J.,Hensler, M.,Wang, K.,Molohon, K.J.,Wang, Y.,Mitchell, D.A.,Nizet, V.,Oldfield, E.
HIV-1 Integrase Inhibitor-Inspired Antibacterials Targeting Isoprenoid Biosynthesis.
ACS Med Chem Lett, 3:402-406, 2012

PubMed Abstract: We report the discovery of antibacterial leads, keto- and diketo-acids, targeting two prenyl transferases: undecaprenyl diphosphate synthase (UPPS) and dehydrosqualene synthase (CrtM). The leads were suggested by the observation that keto- and diketo-acids bind to the active site Mg(2+)/Asp domain in HIV-1 integrase, and similar domains are present in prenyl transferases. We report the x-ray crystallographic structures of one diketo-acid and one keto-acid bound to CrtM, which supports the Mg(2+) binding hypothesis, together with the x-ray structure of one diketo-acid bound to UPPS. In all cases, the inhibitors bind to a farnesyl diphosphate substrate-binding site. Compound 45 had cell growth inhibition MIC(90) values of ~250-500 ng/mL against S. aureus, 500 ng/mL against Bacillus anthracis, 4 μg/mL against Listeria monocytogenes and Enterococcus faecium, and 1 μg/mL against Streptococcus pyogenes M1, but very little activity against E. coli (DH5α, K12) or human cell lines.

PubMed: 22662288
DOI: 10.1021/ml300038t

Experimental method

X-RAY DIFFRACTION (2.114 Å)