5H9D

Crystal structure of Heptaprenyl Diphosphate Synthase from Staphylococcus aureus

Summary for 5H9D

• Entry DOI: 10.2210/pdb5h9d/pdb
• Descriptor: Farnesyl pyrophosphate synthetase, Heptaprenyl diphosphate synthase (HEPPP synthase) subunit 1 family protein, C-terminal peptide from Heptaprenyl diphosphate synthase (HEPPP synthase) subunit 1 family protein, ... (5 entities in total)
• Functional Keywords: metal-binding, substrate binding, acidocalcisomal pyrophosphatase, transferase
• Biological source: Staphylococcus aureus; More
• Total number of polymer chains: 6
• Total formula weight: 121338.39

Authors

Wei, H.L.,Liu, W.D.,Zheng, Y.Y.,Ko, T.P.,Chen, C.C.,Guo, R.T. (deposition date: 2015-12-28, release date: 2016-12-28, Last modification date: 2024-03-20)

Primary citation

Desai, J.,Liu, Y.L.,Wei, H.,Liu, W.,Ko, T.P.,Guo, R.T.,Oldfield, E.
Structure, Function, and Inhibition of Staphylococcus aureus Heptaprenyl Diphosphate Synthase
ChemMedChem, 11:1915-1923, 2016

PubMed Abstract: We report the first structure of heptaprenyl diphosphate synthase from Staphylococcus aureus (SaHepPPS), together with an investigation of its mechanism of action and inhibition. The protein is involved in the formation of menaquinone, a key electron transporter in many bacteria, including pathogens. SaHepPPS consists of a "catalytic " subunit (SaHepPPS-2) having two "DDXXD" motifs and a "regulatory" subunit (SaHepPPS-1) that lacks these motifs. High concentrations of the substrates, isopentenyl diphosphate and farnesyl diphosphate, inhibit the enzyme, which is also potently inhibited by bisphosphonates. The most active inhibitors (Ki ∼200 nm) were N-alkyl analogues of zoledronate containing ∼C6 alkyl side chains. They were modestly active against S. aureus cell growth, and growth inhibition was partially "rescued" by the addition of menaquinone-7. Because SaHepPPS is essential for S. aureus cell growth, its structure is of interest in the context of the development of menaquinone biosynthesis inhibitors as potential antibiotic leads.

PubMed: 27457559
DOI: 10.1002/cmdc.201600311

Experimental method

X-RAY DIFFRACTION (2.68 Å)