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Literature summary for 2.5.1.96 extracted from

  • Liu, C.; Liu, G.; Song, Y.; Yin, F.; Hensler, M.; Jeng, W.; Nizet, V.; Wang, A.; Oldfield, E.
    A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence (2008), Science, 319, 1391-1394.
    View publication on PubMedView publication on EuropePMC

Cloned(Commentary)

Cloned (Comment) Organism
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Staphylococcus aureus

Crystallization (Commentary)

Crystallization (Comment) Organism
native protein to 1.58 A resolution. CrtM crystallizes in the P3221 space group and there is one molecule per asymmetric unit. The overall fold shows similarity to that seen in human squalene synthase. In the complex with substrate analogue farnesyl thiodiphosphate, two farnesyl thiodiphosphate molecules are found in the large central cavity. Their diphosphate head groups interact with three Mg2+ ions, which in turn interact with Asp residues in two conserved Asp-X-X-X-Asp repeats. The space group of the complex is P3121, and there are two molecules per asymmetric unit. In docking studies with phosphonosulfonate inhibitors, only one phosphonosulfonate is bound per CrtM. All three inhibitors tested have different binding modes. 4-(3-phenoxyphenyl)-1-phosphonobutane-1-sulfonic acid binds into the farnesyl thiodiphosphate-1 site with two Mg2+, 4-(4'-butylbiphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid binds into the farnesyl thiodiphosphate-2 site with only one Mg2+, and 4-(biphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid binds into the farnesyl thiodiphosphate-2 site with no Mg2+. The phosphonosulfonate side chains do closely track the locations of the two farnesyl thiodiphosphate inhibitor side chains Staphylococcus aureus

Inhibitors

Inhibitors Comment Organism Structure
4-(3-phenoxyphenyl)-1-phosphonobutane-1-sulfonic acid i.e. BPH-652 Staphylococcus aureus
4-(4'-butylbiphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid i.e. BPH-698 Staphylococcus aureus
4-(4-biphenyl)butyldiphosphonic acid i.e. BPH-674 Staphylococcus aureus
4-(biphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid i.e. BPH-700 Staphylococcus aureus

Organism

Organism UniProt Comment Textmining
Staphylococcus aureus A9JQL9
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Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.0000002
-
4-(4-biphenyl)butyldiphosphonic acid pH not specified in the publication, temperature not specified in the publication Staphylococcus aureus
0.0000015
-
4-(3-phenoxyphenyl)-1-phosphonobutane-1-sulfonic acid pH not specified in the publication, temperature not specified in the publication Staphylococcus aureus
0.000006
-
4-(biphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid pH not specified in the publication, temperature not specified in the publication Staphylococcus aureus
0.000135
-
4-(4'-butylbiphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid pH not specified in the publication, temperature not specified in the publication Staphylococcus aureus