1mrl
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Crystal structure of streptogramin A acetyltransferase with dalfopristin
OverviewOverview
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 StructureAbout this Structure
1MRL is a Single protein structure of sequence from Enterococcus faecium with DOL as ligand. Full crystallographic information is available from OCA.
ReferenceReference
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
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