4ZSY
Pig Brain GABA-AT inactivated by (Z)-(1S,3S)-3-Amino-4-fluoromethylenyl-1-cyclopentanoic acid.
Summary for 4ZSY
| Entry DOI | 10.2210/pdb4zsy/pdb |
| Descriptor | 4-aminobutyrate aminotransferase, mitochondrial, FE2/S2 (INORGANIC) CLUSTER, (1S)-4-[({3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]pyridin-4-yl}methyl)amino]cyclopent-3-ene-1,3-dicarboxylic acid, ... (5 entities in total) |
| Functional Keywords | gaba aminotransferase, amino-4-fluoromethylenyl-1-cyclopentanoic acid, inactivation, mechanism-based, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Sus scrofa (Pig) |
| Total number of polymer chains | 4 |
| Total formula weight | 211107.88 |
| Authors | Wu, R.,Lee, H.,Le, H.V.,Doud, E.,Sanishvili, R.,Compton, P.,Kelleher, N.L.,Silverman, R.B.,Liu, D. (deposition date: 2015-05-14, release date: 2015-07-08, Last modification date: 2024-03-06) |
| Primary citation | Lee, H.,Le, H.V.,Wu, R.,Doud, E.,Sanishvili, R.,Kellie, J.F.,Compton, P.D.,Pachaiyappan, B.,Liu, D.,Kelleher, N.L.,Silverman, R.B. Mechanism of Inactivation of GABA Aminotransferase by (E)- and (Z)-(1S,3S)-3-Amino-4-fluoromethylenyl-1-cyclopentanoic Acid. Acs Chem.Biol., 10:2087-2098, 2015 Cited by PubMed Abstract: When γ-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. PubMed: 26110556DOI: 10.1021/acschembio.5b00212 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
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