2p7l
From Proteopedia
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Crystal structure of monoclinic form of genomically encoded fosfomycin resistance protein, FosX, from Listeria monocytogenes at pH 5.75
Overview
The fosfomycin resistance protein, FosX, catalyzes the hydration of the antibiotic fosfomycin, (1R,2S)-epoxypropylphosphonic acid. Genes encoding the enzyme are found in several pathogenic microorganisms. The structure and mechanism of action of the genomically encoded FosX enzyme from Listeria monocytogenes (FosXLMATCC) obtained from the American Type Culture Collection are reported. The gene harbors 31 point mutations, and as a consequence, the protein differs in 10 amino acid residues from the previously reported FosX encoded in the genome of the EGD strain of L. monocytogenes (FosXLMEGD). The FosXLMATCC enzyme is shown to catalyze the addition of water to the C1 position of the antibiotic with inversion of configuration at C1. The reaction involves Mn(II) activation of the oxirane oxygen and E44 acting as a general base. The structure of the enzyme has been determined from six different crystal forms of the protein. The structures of the enzyme without metal bound are similar but differ in the loop regions. Perhaps the most informative structure is the one with the product bound. This structure shows that the phosphonate group of the product is bound in an orientation that is different than that of fosfomycin bound to the related enzyme, FosA. The implication is that the substrate may also be bound in a different orientation in FosX. A high-resolution structure (1.44 A resolution) of the enzyme reveals a unique conformation in which the C-terminal tail of the protein coordinates to the Mn(II) center via the carboxylate of E126. The kinetic characterization of the E126Q mutant indicates that this conformation of the protein is probably not relevant to the function of the enzyme. Kinetic analysis of mutants of active site residue E44 is consistent with its proposed roll as a general base catalyst in the addition of water to the antibiotic.
About this Structure
2P7L is a Single protein structure of sequence from Listeria monocytogenes with as ligand. Full crystallographic information is available from OCA.
Reference
Structure and mechanism of the genomically encoded fosfomycin resistance protein, FosX, from Listeria monocytogenes., Fillgrove KL, Pakhomova S, Schaab MR, Newcomer ME, Armstrong RN, Biochemistry. 2007 Jul 10;46(27):8110-20. Epub 2007 Jun 13. PMID:17567049
Page seeded by OCA on Thu Feb 21 18:26:45 2008
