6KIY

Crystal structure of a thermostable aldo-keto reductase Tm1743 in complex with inhibitor Epalrestat

Summary for 6KIY

• Entry DOI: 10.2210/pdb6kiy/pdb
• Related: 6KIK
• Descriptor: Oxidoreductase, aldo/keto reductase family, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, {5-[(2E)-2-methyl-3-phenylprop-2-en-1-ylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl}acetic acid, ... (4 entities in total)
• Functional Keywords: aldo-ketone reductase, epalrestat, competitive inhibitor, nadph, oxidoreductase
• Biological source: Thermotoga maritima MSB8
• Total number of polymer chains: 1
• Total formula weight: 32552.83

Authors

Zhang, C.Y.,Liu, X.M.,Wang, C.,Min, Z.Z.,Xu, X.L. (deposition date: 2019-07-20, 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

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: 31573681
DOI: 10.1002/1873-3468.13630

Experimental method

X-RAY DIFFRACTION (1.9 Å)