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1mrl
From Proteopedia
(New page: 200px<br /><applet load="1mrl" size="450" color="white" frame="true" align="right" spinBox="true" caption="1mrl, resolution 2.80Å" /> '''Crystal structure of...) |
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| - | [[Image:1mrl.gif|left|200px]]<br /><applet load="1mrl" size=" | + | [[Image:1mrl.gif|left|200px]]<br /><applet load="1mrl" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1mrl, resolution 2.80Å" /> | caption="1mrl, resolution 2.80Å" /> | ||
'''Crystal structure of streptogramin A acetyltransferase with dalfopristin'''<br /> | '''Crystal structure of streptogramin A acetyltransferase with dalfopristin'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Synercid, a new semisynthetic streptogramin-derived antibiotic containing | + | 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== | ==About this Structure== | ||
| - | 1MRL is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Enterococcus_faecium Enterococcus faecium] with DOL as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1MRL is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Enterococcus_faecium Enterococcus faecium] with <scene name='pdbligand=DOL:'>DOL</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MRL OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Courvalin, P.]] | [[Category: Courvalin, P.]] | ||
| - | [[Category: Kehoe, L | + | [[Category: Kehoe, L E.]] |
| - | [[Category: Murray, I | + | [[Category: Murray, I A.]] |
| - | [[Category: Rafferty, J | + | [[Category: Rafferty, J B.]] |
[[Category: Snidwongse, J.]] | [[Category: Snidwongse, J.]] | ||
[[Category: DOL]] | [[Category: DOL]] | ||
[[Category: left-handed parallel beta-helix domain]] | [[Category: left-handed parallel beta-helix domain]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:58:24 2008'' |
Revision as of 11:58, 21 February 2008
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Crystal structure of streptogramin A acetyltransferase with dalfopristin
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
1MRL is a Single protein structure of sequence from Enterococcus faecium with as ligand. 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
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