4zsw

Pig Brain GABA-AT inactivated by (E)-(1S,3S)-3-Amino-4-fluoromethylenyl-1-cyclopentanoic acid

spinqualitylabelsall models 4zsw, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4zsw is a 4 chain structure with sequence from Sus scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.7Å Ligands: ACT, FES, GOL, RW2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GABT_PIG Catalyzes the conversion of gamma-aminobutyrate and L-beta-aminoisobutyrate to succinate semialdehyde and methylmalonate semialdehyde, respectively. Can also convert delta-aminovalerate and beta-alanine. Publication Abstract from PubMed When gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, falls below a threshold level, seizures occur. One approach to raise GABA concentrations is to inhibit GABA aminotransferase (GABA-AT), a pyridoxal 5'-phosphate-dependent enzyme that degrades GABA. We have previously developed (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115), which is 186 times more efficient in inactivating GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. We also developed (E)- and (Z)-(1S,3S)-3-amino-4-fluoromethylenyl-1-cyclopentanoic acid (1 and 2, respectively), monofluorinated analogs of CPP-115, which are comparable to vigabatrin in inactivating GABA-AT. Here, we report the mechanism of inactivation of GABA-AT by 1 and 2. Both produce a metabolite that induces disruption of the Glu270-Arg445 salt bridge to accommodate interaction between the metabolite formyl group and Arg445. This is the second time that Arg445 has interacted with a ligand and is involved in GABA-AT inactivation, thereby confirming the importance of Arg445 in future inactivator design. Mechanism of Inactivation of GABA Aminotransferase by (E)- and (Z)-(1S,3S)-3-Amino-4-fluoromethylenyl-1-cyclopentanoic Acid.,Lee H, Le HV, Wu R, Doud E, Sanishvili R, Kellie JF, Compton PD, Pachaiyappan B, Liu D, Kelleher NL, Silverman RB ACS Chem Biol. 2015 Jul 6. PMID:26110556 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aminotransferase 3D structures

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