2fmn

Ala177Val mutant of E. coli Methylenetetrahydrofolate Reductase complex with LY309887

spinqualitylabelsall models 2fmn, resolution 2.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2fmn is a 3 chain structure with sequence from "bacillus_coli"_migula_1895 "bacillus coli" migula 1895. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 4HF, FAD Related: 2fmo Gene: metF ("Bacillus coli" Migula 1895) Activity: Methylenetetrahydrofolate reductase (NAD(P)H), with EC number 1.5.1.20 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [METF_ECOLI] Methylenetetrahydrofolate reductase required to generate the methyl groups necessary for methionine synthetase to convert homocysteine to methionine. 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 In human methylenetetrahydrofolate reductase (MTHFR) the Ala222Val (677C-->T) polymorphism encodes a heat-labile gene product that is associated with elevated levels of homocysteine and possibly with risk for cardiovascular disease. Generation of the equivalent Ala to Val mutation in Escherichia coli MTHFR, which is 30% identical to the catalytic domain of the human enzyme, creates a protein with enhanced thermolability. In both human and E. coli MTHFR, the A --> V mutation increases the rate of dissociation of FAD, and in both enzymes, loss of FAD is linked to changes in quaternary structure [Yamada, K., Chen, Z., Rozen, R., and Matthews, R. G. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 14853-14858; Guenther, B. D., Sheppard, C. A., Tran, P., Rozen, R., Matthews, R. G., and Ludwig, M. L. (1999) Nat. Struct. Biol. 6, 359-365]. Folates have been shown to protect both human and bacterial enzymes from loss of FAD. Despite its effect on affinity for FAD, the A --> V mutation is located at the bottom of the (betaalpha)(8) barrel of the catalytic domain in a position that does not contact the bound FAD prosthetic group. Here we report the structures of the Ala177Val mutant of E. coli MTHFR and of its complex with the 5,10-dideazafolate analogue, LY309887, and suggest mechanisms by which the mutation may perturb FAD binding. Helix alpha5, which immediately precedes the loop bearing the mutation, carries several residues that interact with FAD, including Asn168, Arg171, and Lys172. In the structures of the mutant enzyme this helix is displaced, perturbing protein-FAD interactions. In the complex with LY309887, the pterin-like ring of the analogue stacks against the si face of the flavin and is secured by hydrogen bonds to residues Gln183 and Asp120 that adjoin this face. The direct interactions of bound folate with the cofactor provide one mechanism for linkage between binding of FAD and folate binding that could account in part for the protective action of folates. Conformation changes induced by folate binding may also suppress dissociation of FAD. Structural perturbations in the Ala --> Val polymorphism of methylenetetrahydrofolate reductase: how binding of folates may protect against inactivation.,Pejchal R, Campbell E, Guenther BD, Lennon BW, Matthews RG, Ludwig ML Biochemistry. 2006 Apr 18;45(15):4808-18. PMID:16605249 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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