4l5z

Crystal structure of the Candida albicans Methionine Synthase in complex with Homocysteine

spinqualitylabelsall models 4l5z, resolution 2.18Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4l5z is a 1 chain structure with sequence from Candida albicans SC5314. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: HCS, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function METE_CANAL Catalyzes the transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine resulting in methionine formation.[HAMAP-Rule:MF_00172] Publication Abstract from PubMed The cobalamin-independent methionine synthase from Candida albicans, known as Met6p, is a 90-kDa enzyme that consists of two (betaalpha)8 barrels. The active site is located between the two domains and has binding sites for a zinc ion and substrates l-homocysteine and 5-methyl-tetrahydrofolate-glutamate3. Met6p catalyzes transfer of the methyl group of 5-methyl-tetrahydrofolate-glutamate3 to the l-homocysteine thiolate to generate methionine. Met6p is essential for fungal growth, and we currently pursue it as an antifungal drug design target. Here we report the binding of l-homocysteine, methionine, and several folate analogs. We show that binding of l-homocysteine or methionine results in conformational rearrangements at the amino acid binding pocket, moving the catalytic zinc into position to activate the thiol group. We also map the folate binding pocket and identify specific binding residues, like Asn126, whose mutation eliminates catalytic activity. We also report the development of a robust fluorescence-based activity assay suitable for high-throughput screening. We use this assay and an X-ray structure to characterize methotrexate as a weak inhibitor of fungal Met6p. Structural analysis of a fungal methionine synthase with substrates and inhibitors.,Ubhi D, Kago G, Monzingo AF, Robertus JD J Mol Biol. 2014 Apr 17;426(8):1839-47. doi: 10.1016/j.jmb.2014.02.006. Epub 2014, Feb 11. PMID:24524835 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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