6egr | pdb_00006egr

Crystal structure of Citrobacter freundii methionine gamma-lyase with V358Y replacement

spinqualitylabelsall models 6egr, resolution 1.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6egr is a 1 chain structure with sequence from "bacterium_freundii"_braak_1928 "bacterium freundii" braak 1928. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: PEG, PGE, PLP NonStd Res: CSO Gene: AN672_11005, BED45_02240, BEH73_12300, CfB38_0199, HMPREF3212_02785, TO64_18625 ("Bacterium freundii" Braak 1928) Activity: Methionine gamma-lyase, with EC number 4.4.1.11 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Methionine deprivation of cancer cells, which are deficient in methionine biosynthesis, has been envisioned as a therapeutic strategy to reduce cancer cell viability. Methionine gamma-lyase (MGL), an enzyme that degrades methionine, has been exploited to selectively remove the amino acid from cancer cell environment. In order to increase MGL catalytic activity, we performed sequence and structure conservation analysis of MGLs from various microorganisms. Whereas most of the residues in the active site and at the dimer interface were found to be conserved, residues located in the C-terminal flexible loop, forming a wall of the active site entry channel, were found to be variable. Therefore, we carried out site-saturation mutagenesis at four independent positions of the C-terminal flexible loop, P357, V358, P360 and A366 of MGL from Citrobacter freundii, generating libraries that were screened for activity. Among the active variants, V358Y exhibits a 1.9-fold increase in the catalytic rate and a 3-fold increase in KM, resulting in a catalytic efficiency similar to wild type MGL. V358Y cytotoxic activity was assessed towards a panel of cancer and nonmalignant cell lines and found to exhibit IC50 lower than the wild type. The comparison of the 3D-structure of V358Y MGL with other MGL available structures indicates that the C-terminal loop is either in an open or closed conformation that does not depend on the amino acid at position 358. Nevertheless, mutations at this position allosterically affects catalysis. Engineering methionine gamma-lyase from Citrobacter freundii for anticancer activity.,Raboni S, Revtovich S, Demitri N, Giabbai B, Storici P, Cocconcelli C, Faggiano S, Rosini E, Pollegioni L, Galati S, Buschini A, Morozova E, Kulikova V, Nikulin A, Gabellieri E, Cioni P, Demidkina T, Mozzarelli A Biochim Biophys Acta Proteins Proteom. 2018 Dec;1866(12):1260-1270. doi:, 10.1016/j.bbapap.2018.09.011. Epub 2018 Sep 27. PMID:30268810 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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