2ZY1

Crystal structure of the C(30) carotenoid dehydrosqualene synthase from Staphylococcus aureus complexed with bisphosphonate BPH-830

Summary for 2ZY1

• Entry DOI: 10.2210/pdb2zy1/pdb
• Related: 2ZCO 2ZCP 2ZCQ 2ZCR 2ZCS
• Descriptor: Dehydrosqualene synthase, dipotassium (2-oxo-2-{[3-(3-phenoxyphenyl)propyl]amino}ethyl)phosphonate (3 entities in total)
• Functional Keywords: crtm, carotenoid biosynthesis, staphyloxanthin biosynthesis, transferase, head-to-head condensation, inhibitor
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 1
• Total formula weight: 35213.00

Authors

Liu, C.I.,Jeng, W.Y.,Wang, A.H.J.,Oldfield, E. (deposition date: 2009-01-10, release date: 2009-09-01, Last modification date: 2023-11-01)

Primary citation

Song, Y.,Liu, C.I.,Lin, F.Y.,No, J.H.,Hensler, M.,Liu, Y.L.,Jeng, W.Y.,Low, J.,Liu, G.Y.,Nizet, V.,Wang, A.H.J.,Oldfield, E.
Inhibition of staphyloxanthin virulence factor biosynthesis in Staphylococcus aureus: in vitro, in vivo, and crystallographic results.
J.Med.Chem., 52:3869-3880, 2009

PubMed Abstract: The gold color of Staphylococcus aureus is derived from the carotenoid staphyloxanthin, a virulence factor for the organism. Here, we report the synthesis and activity of a broad variety of staphyloxanthin biosynthesis inhibitors that inhibit the first committed step in its biosynthesis, condensation of two farnesyl diphosphate (FPP) molecules to dehydrosqualene, catalyzed by the enzyme dehydrosqualene synthase (CrtM). The most active compounds are phosphonoacetamides that have low nanomolar K(i) values for CrtM inhibition and are active in whole bacterial cells and in mice, where they inhibit S. aureus disease progression. We also report the X-ray crystallographic structure of the most active compound, N-3-(3-phenoxyphenyl)propylphosphonoacetamide (IC(50) = 8 nM, in cells), bound to CrtM. The structure exhibits a complex network of hydrogen bonds between the polar headgroup and the protein, while the 3-phenoxyphenyl side chain is located in a hydrophobic pocket previously reported to bind farnesyl thiodiphosphate (FsPP), as well as biphenyl phosphonosulfonate inhibitors. Given the good enzymatic, whole cell, and in vivo pharmacologic activities, these results should help guide the further development of novel antivirulence factor-based therapies for S. aureus infections.

PubMed: 19456099
DOI: 10.1021/jm9001764

Experimental method

X-RAY DIFFRACTION (1.78 Å)