2z2p | pdb_00002z2p

Crystal Structure of catalytically inactive H270A virginiamycin B lyase from Staphylococcus aureus with Quinupristin

spinqualitylabelsall models 2z2p, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2z2p is a 4 chain structure with sequence from Staphylococcus aureus and Streptomyces graminofaciens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.8Å Ligands: 004, DBB, DOL, MG, MHT, MHU, MHV, MHW Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function VGB_STAAU Inactivates the type B streptogramin antibiotics by linearizing the lactone ring at the ester linkage, generating a free phenylglycine carboxylate and converting the threonyl moiety into 2-amino-butenoic acid. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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