1nki

CRYSTAL STRUCTURE OF THE FOSFOMYCIN RESISTANCE PROTEIN A (FOSA) CONTAINING BOUND PHOSPHONOFORMATE

spinqualitylabelsall models 1nki, resolution 0.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1nki is a 2 chain structure with sequence from Pseudomonas aeruginosa PAO1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 0.95Å Ligands: K, MN, PPF Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function FOSA_PSEAE Metalloglutathione transferase which confers resistance to fosfomycin by catalyzing the addition of glutathione to fosfomycin. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Fosfomycin [(1R,2S)-epoxypropylphosphonic acid] is a simple phosphonate found to have antibacterial activity against both Gram-positive and Gram-negative microorganisms. Early resistance to the clinical use of the antibiotic was linked to a plasmid-encoded resistance protein, FosA, that catalyzes the addition of glutathione to the oxirane ring, rendering the antibiotic inactive. Subsequent studies led to the discovery of a genomically encoded homologue in the pathogen Pseudomonas aeruginosa. The proteins are Mn(II)-dependent enzymes where the metal is proposed to act as a Lewis acid stabilizing the negative charge that develops on the oxirane oxygen in the transition state. Several simple phosphonates, including the antiviral compound phosphonoformate (K(i) = 0.4 +/- 0.1 microM, K(d) approximately 0.2 microM), are shown to be inhibitors of FosA. The crystal structure of FosA from P. aeruginosa with phosphonoformate bound in the active site has been determined at 0.95 A resolution and reveals that the inhibitor forms a five-coordinate complex with the Mn(II) center with a geometry similar to that proposed for the transition state of the reaction. Binding studies show that phosphonoformate has a near-diffusion-controlled on rate (k(on) approximately 10(7)-10(8) M(-1) s(-1)) and an off rate (k(off) = 5 s(-1)) that is slower than that for fosfomycin (k(off) = 30 s(-1)). Taken together, these data suggest that the FosA-catalyzed reaction has a very early transition state and phosphonoformate acts as a minimal transition state analogue inhibitor. Phosphonoformate: a minimal transition state analogue inhibitor of the fosfomycin resistance protein, FosA.,Rigsby RE, Rife CL, Fillgrove KL, Newcomer ME, Armstrong RN Biochemistry. 2004 Nov 2;43(43):13666-73. PMID:15504029 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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