2z2p
|
Crystal Structure of catalytically inactive H270A virginiamycin B lyase from Staphylococcus aureus with Quinupristin
OverviewOverview
The streptogramin combination therapy of quinupristin-dalfopristin, (Synercid) is used to treat infections caused by bacterial pathogens, such, as methicillin-resistant Staphylococcus aureus and vancomycin-resistant, Enterococcus faecium. However, the effectiveness of this therapy is being, compromised because of an increased incidence of streptogramin resistance., One of the clinically observed mechanisms of resistance is enzymatic, inactivation of the type B streptogramins, such as quinupristin, by a, streptogramin B lyase, i.e., virginiamycin B lyase (Vgb). The enzyme, catalyzes the linearization of the cyclic antibiotic via a cleavage that, requires a divalent metal ion. Here, we present crystal structures of Vgb, from S. aureus in its apoenzyme form and in complex with quinupristin and, Mg2+ at 1.65- and 2.8-A resolution, respectively. The fold of the enzyme, is that of a seven-bladed beta-propeller, although the sequence reveals no, similarity to other known members of this structural family. Quinupristin, binds to a large depression on the surface of the enzyme, where it, predominantly forms van der Waals interactions. Validated by site-directed, mutagenesis studies, a reaction mechanism is proposed in which the initial, abstraction of a proton is facilitated by a Mg2+ -linked conjugated, system. Analysis of the Vgb-quinupristin structure and comparison with the, complex between quinupristin and its natural target, the 50S ribosomal, subunit, reveals features that can be exploited for developing, streptogramins that are impervious to Vgb-mediated resistance.
About this StructureAbout this Structure
2Z2P is a Single protein structure of sequence from Staphylococcus aureus with , and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for streptogramin B resistance in Staphylococcus aureus by virginiamycin B lyase., Korczynska M, Mukhtar TA, Wright GD, Berghuis AM, Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10388-93. Epub 2007 Jun 11. PMID:17563376
Page seeded by OCA on Wed Jan 23 11:57:54 2008