2z2n: Difference between revisions

Revision as of 19:59, 21 February 2008

Crystal Structure of selenomethionine substituted virginiamycin B lyase from Staphylococcus aureus

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

2Z2N is a Single protein structure of sequence from Staphylococcus aureus with as ligand. 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 Thu Feb 21 18:59:47 2008

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 ==Overview==
-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.
+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 Structure==
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 [[Category: Single protein]]
 [[Category: Staphylococcus aureus]]
-[[Category: Berghuis, A.M.]]
+[[Category: Berghuis, A M.]]
 [[Category: Korczynska, M.]]
 [[Category: CL]]
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 [[Category: virginiamycin b lyase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 11:57:52 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:59:47 2008''