2XH1

Crystal structure of human KAT II-inhibitor complex

Summary for 2XH1

• Entry DOI: 10.2210/pdb2xh1/pdb
• Related: 2VGZ
• Descriptor: KYNURENINE/ALPHA-AMINOADIPATE AMINOTRANSFERASE, MITOCHONDRIAL, (3S)-10-(4-AMINOPIPERAZIN-1-YL)-9-FLUORO-7-HYDROXY-3-METHYL-2,3-DIHYDRO-8H-[1,4]OXAZINO[2,3,4-IJ]QUINOLINE-6-CARBOXYLATE, PYRIDOXAL-5'-PHOSPHATE, ... (6 entities in total)
• Functional Keywords: transferase, covalent inhibition
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Mitochondrion (Potential): Q8N5Z0
• Total number of polymer chains: 2
• Total formula weight: 96234.70

Authors

Rossi, F.,Casazza, V.,Garavaglia, S.,Sathyasaikumar, K.V.,Schwarcz, R.,Kojima, S.I.,Okuwaki, K.,Ono, S.I.,Kajii, Y.,Rizzi, M. (deposition date: 2010-06-08, release date: 2010-07-28, Last modification date: 2023-12-20)

Primary citation

Rossi, F.,Casazza, V.,Garavaglia, S.,Sathyasaikumar, K.V.,Schwarcz, R.,Kojima, S.I.,Okuwaki, K.,Ono, S.I.,Kajii, Y.,Rizzi, M.
Crystal Structure-Based Selective Targeting of the Pyridoxal 5'-Phsosphate Dependent Enzyme Kynurenine Aminotransferase II for Cognitive Enhancement
J.Med.Chem., 53:5684-, 2010

PubMed Abstract: Fluctuations in the brain levels of the neuromodulator kynurenic acid may control cognitive processes and play a causative role in several catastrophic brain diseases. Elimination of the pyridoxal 5'-phosphate dependent enzyme kynurenine aminotransferase II reduces cerebral kynurenic acid synthesis and has procognitive effects. The present description of the crystal structure of human kynurenine aminotransferase II in complex with its potent and specific primary amine-bearing fluoroquinolone inhibitor (S)-(-)-9-(4-aminopiperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-azaphenalene-5-carboxylic acid (BFF-122) should facilitate the structure-based development of cognition-enhancing drugs. From a medicinal chemistry perspective our results demonstrate that the issue of inhibitor specificity for highly conserved PLP-dependent enzymes could be successfully addressed.

PubMed: 20684605
DOI: 10.1021/JM100464K

Experimental method

X-RAY DIFFRACTION (2.1 Å)