5vwq

E.coli Aspartate aminotransferase-(1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid (FCP)

spinqualitylabelsall models 5vwq, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5vwq is a 4 chain structure with sequence from Escherichia coli K-12. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: PMP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function AAT_ECOLI Publication Abstract from PubMed Potent mechanism-based inactivators can be rationally designed against PLP-dependent drug targets, such as ornithine aminotransferase (OAT) or gamma-aminobutyric acid aminotransferase (GABA-AT). An important challenge, however, is the lack of selectivity towards other PLP-dependent off-target enzymes, because of similarities in mechanisms of all PLP-dependent aminotransferase reactions. On the basis of complex crystal structures, we investigate the inactivation mechanism of OAT, a hepatocellular carcinoma (HCC) target, by (1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid (FCP), a known inactivator of GABA-AT. A crystal structure of OAT and FCP showed the formation of a ternary adduct. This adduct can be rationalized as occurring via an enamine mechanism of inactivation similar to that reported for GABA-AT. However, the crystal structure of an off-target PLP-dependent enzyme, aspartate aminotransferase (Asp-AT), in complex with FCP, along with the results of attempted inhibition assays, suggest that FCP is not an inactivator of Asp-AT, but rather an alternate substrate. Turnover of FCP by Asp-AT is also supported by high-resolution mass spectrometry. In comparison to the inactivation mechanisms of FCP against OAT and GABA-AT, the obtained results provide evidence that a desirable selectivity of inactivation could be achieved, taking advantage of subtle structural and mechanistic differences between a drug-target and an off-target enzyme, despite their largely similar substrate binding sites and catalytic mechanisms. Selective Targeting by a Mechanism-based Inactivator against PLP-Dependent Enzymes: Mechanisms of Inactivation and Alternative Turnover.,Mascarenhas R, Le HV, Clevenger KD, Lehrer HJ, Ringe D, Kelleher NL, Silverman RB, Liu D Biochemistry. 2017 Aug 17. doi: 10.1021/acs.biochem.7b00499. PMID:28816437 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aspartate aminotransferase 3D structures

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