1X97
Crystal structure of Aldose Reductase complexed with 2R4S (Stereoisomer of Fidarestat, 2S4S)
Summary for 1X97
| Entry DOI | 10.2210/pdb1x97/pdb |
| Related | 1PWM 1X96 1X98 |
| Descriptor | Aldose Reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, (2R,4S)-2-AMINOFORMYL-6-FLUORO-SPIRO[CHROMAN-4,4'-IMIDAZOLIDINE]-2',5'-DIONE, ... (4 entities in total) |
| Functional Keywords | eight strandard alpha/beta barrel, active site, the c-terminal end of the barrel, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm: P15121 |
| Total number of polymer chains | 1 |
| Total formula weight | 36920.97 |
| Authors | El-Kabbani, O.,Darmanin, C.,Oka, M.,Schulze-Briese, C.,Tomizaki, T.,Hazemann, I.,Mitschler, A.,Podjarny, A. (deposition date: 2004-08-19, release date: 2004-09-07, Last modification date: 2023-10-25) |
| Primary citation | El-Kabbani, O.,Darmanin, C.,Oka, M.,Schulze-Briese, C.,Tomizaki, T.,Hazemann, I.,Mitschler, A.,Podjarny, A. High-Resolution Structures of Human Aldose Reductase Holoenzyme in Complex with Stereoisomers of the Potent Inhibitor Fidarestat: Stereospecific Interaction between the Enzyme and a Cyclic Imide Type Inhibitor J.Med.Chem., 47:4530-4537, 2004 Cited by PubMed Abstract: Structure determinations of human aldose reductase holoenzyme in complex with the 2S4R-,2R4S- and 2R4R-isomers of the potent inhibitor Fidarestat ((2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazoline]-2-carboxamide) were carried out in order to elucidate the binding modes responsible for the differences in their inhibitory potencies. In the complex structure with the 2R4S-isomer the cyclic imide moiety formed hydrogen bonds with the side-chains of Trp111, Tyr48 and His110. In the attempt to determine the complex structure with the least potent 2R4R-isomer this ligand was not observed, and instead, the active site was simultaneously occupied by two citrate molecules (occupancies of 60% and 40%). In the case of 2S4R, the active site was occupied by a citrate molecule which anchors the 2S4R-isomer from its carbamoyl group. The structures of the complexes suggest that the differences in the interactions between the cyclic imide rings and carbamoyl groups of the compounds with residues His110, Trp111, Trp219 and Cys298 account for differences in their inhibitory potencies. PubMed: 15317464DOI: 10.1021/jm0497794 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.4 Å) |
Structure validation
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