6KIK
Crystal structure of a thermostable aldo-keto reductase Tm1743 in complex with inhibitor tolrestat
Summary for 6KIK
| Entry DOI | 10.2210/pdb6kik/pdb |
| Descriptor | Oxidoreductase, aldo/keto reductase family, TOLRESTAT (3 entities in total) |
| Functional Keywords | aldo-ketone reductase, tolrestat, competitive inhibitor, oxidoreductase |
| Biological source | Thermotoga maritima (strain ATCC 43589 / MSB8 / DSM 3109 / JCM 10099) |
| Total number of polymer chains | 1 |
| Total formula weight | 31847.37 |
| Authors | Zhang, C.Y.,Liu, X.M.,Wang, C.,Tang, W.R. (deposition date: 2019-07-18, release date: 2019-09-25, Last modification date: 2023-11-22) |
| Primary citation | Zhang, C.,Min, Z.,Liu, X.,Wang, C.,Wang, Z.,Shen, J.,Tang, W.,Zhang, X.,Liu, D.,Xu, X. Tolrestat acts atypically as a competitive inhibitor of the thermostable aldo-keto reductase Tm1743 from Thermotoga maritima. Febs Lett., 594:564-580, 2020 Cited by PubMed Abstract: Tolrestat and epalrestat have been characterized as noncompetitive inhibitors of aldo-ketone reductase 1B1 (AKR1B1), a leading drug target for the treatment of type 2 diabetes complications. However, clinical applications are limited for most AKR1B1 inhibitors due to adverse effects of cross-inhibition with other AKRs. Here, we report an atypical competitive binding and inhibitory effect of tolrestat on the thermostable AKR Tm1743 from Thermotoga maritima. Analysis of the Tm1743 crystal structure in complex with tolrestat alone and epalrestat-NADP shows that tolrestat, but not epalrestat, binding triggers dramatic conformational changes in the anionic site and cofactor binding pocket that prevents accommodation of NADP . Enzymatic and molecular dynamics simulation analyses further confirm tolrestat as a competitive inhibitor of Tm1743. PubMed: 31573681DOI: 10.1002/1873-3468.13630 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.601 Å) |
Structure validation
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