2Z2P

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

2Z2P の概要

• エントリーDOI: 10.2210/pdb2z2p/pdb
• 関連するPDBエントリー: 1SM1
• 関連するBIRD辞書のPRD_ID: PRD_000505
• 分子名称: Virginiamycin B lyase, Quinupristin, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: quinupristin, dalfopristin, streptogramin, synercid, lyase-antibiotic complex, antibiotic resistance, antibiotic, virginiamycin b lyase, virginiamycin b hydrolase, lyase/antibiotic
• 由来する生物種: Staphylococcus aureus; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 69595.87

構造登録者

Korczynska, M.,Berghuis, A.M. (登録日: 2007-05-25, 公開日: 2007-06-19, 最終更新日: 2024-07-10)

主引用文献

Korczynska, M.,Mukhtar, T.A.,Wright, G.D.,Berghuis, A.M.
Structural Basis for Streptogramin B Resistance in Staphylococcus Aureus by Virginiamycin B Lyase
Proc.Natl.Acad.Sci.USA, 104:10388-, 2007

PubMed Abstract: 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.

PubMed: 17563376
DOI: 10.1073/PNAS.0701809104

実験手法

X-RAY DIFFRACTION (2.8 Å)