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| [[Image:1mr7.gif|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_1mr7| PDB=1mr7 | SCENE= }} | | {{STRUCTURE_1mr7| PDB=1mr7 | SCENE= }} |
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| '''Crystal Structure of Streptogramin A Acetyltransferase'''
| | ===Crystal Structure of Streptogramin A Acetyltransferase=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_12771141}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 12771141 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_12771141}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Snidwongse, J.]] | | [[Category: Snidwongse, J.]] |
| [[Category: Left-handed parallel beta-helix domain]] | | [[Category: Left-handed parallel beta-helix domain]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 01:37:29 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 12:24:49 2008'' |
