1mr7
From Proteopedia
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Crystal Structure of Streptogramin A Acetyltransferase
Overview
Synercid, a new semisynthetic streptogramin-derived antibiotic containing, dalfopristin and quinupristin, is used in treatment of life-threatening, infections caused by glycopeptide-resistant Enterococcus faecium and other, bacterial pathogens. However, dissemination of genes encoding, virginiamycin acetyltransferases, enzymes that confer resistance to, streptogramins, threatens to limit the medical utility of the, quinupristin-dalfopristin combination. Here we present structures of, virginiamycin acetyltransferase D (VatD) determined at 1.8 A resolution in, the absence of ligands, at 2.8 A resolution bound to dalfopristin, and at, 3.0 A resolution in the presence of acetyl-coenzyme A. Dalfopristin is, bound by VatD in a similar conformation to that described previously for, the streptogramin virginiamycin M1. However, specific interactions with, the substrate are altered as a consequence of a conformational change in, the pyrollidine ring that is propagated to adjacent constituents of the, dalfopristin macrocycle. Inactivation of dalfopristin involves acetyl, transfer from acetyl-coenzyme A to the sole (O-18) hydroxy group of the, antibiotic that lies close to the side chain of the strictly conserved, residue, His-82. Replacement of residue 82 by alanine is accompanied by a, fall in specific activity of >105-fold, indicating that the imidazole, moiety of His-82 is a major determinant of catalytic rate enhancement by, VatD. The structure of the VatD-dalfopristin complex can be used to, predict positions where further structural modification of the drug might, preclude enzyme binding and thereby circumvent Synercid resistance.
About this Structure
1MR7 is a Single protein structure of sequence from Enterococcus faecium. Full crystallographic information is available from OCA.
Reference
Structural basis of Synercid (quinupristin-dalfopristin) resistance in Gram-positive bacterial pathogens., Kehoe LE, Snidwongse J, Courvalin P, Rafferty JB, Murray IA, J Biol Chem. 2003 Aug 8;278(32):29963-70. Epub 2003 May 27. PMID:12771141
Page seeded by OCA on Tue Nov 20 21:38:53 2007
