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首页> 外文期刊>Acta crystallographica.Section D Biological crystallography. >Identification of a novel polyfluorinated compound as a lead to inhibit the human enzymes aldose reductase and AKR1B10: Structure determination of both ternary complexes and implications for drug design
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Identification of a novel polyfluorinated compound as a lead to inhibit the human enzymes aldose reductase and AKR1B10: Structure determination of both ternary complexes and implications for drug design

机译：小说polyfluorinated化合物的识别作为人类酶导致抑制醛糖还原酶和AKR1B10:结构的决心三元复合物和对药物的影响设计

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摘要

Aldo-keto reductases (AKRs) are mostly monomeric enzymes which fold into a highly conserved (α/β)8 barrel, while their substrate specificity and inhibitor selectivity are determined by interaction with residues located in three highly variable external loops. The closely related human enzymes aldose reductase (AR or AKR1B1) and AKR1B10 are of biomedical interest because of their involvement in secondary diabetic complications (AR) and in cancer, e.g. hepatocellular carcinoma and smoking-related lung cancer (AKR1B10). After characterization of the IC50 values of both AKRs with a series of polyhalogenated compounds, 2,2′,3,3′,5,5′,6,6′- octafluoro-4,4′-biphenyldiol (JF0064) was identified as a lead inhibitor of both enzymes with a new scaffold (a 1,1′-biphenyl-4,4′-diol). An ultrahigh-resolution X-ray structure of the AR-NADP+-JF0064 complex has been determined at 0.85 ? resolution, allowing it to be observed that JF0064 interacts with the catalytic residue Tyr48 through a negatively charged hydroxyl group (i.e. the acidic phenol). The non-competitive inhibition pattern observed for JF0064 with both enzymes suggests that this acidic hydroxyl group is also present in the case of AKR1B10. Moreover, the combination of surface lysine methylation and the introduction of K125R and V301L mutations enabled the determination of the X-ray crystallo-graphic structure of the corresponding AKR1B10-NADP+-JF0064 complex. Comparison of the two structures has unveiled some important hints for subsequent structure-based drug-design efforts.
机译：Aldo-keto还原酶(AKRs)大多是单节的折叠成一个高度保守的酶(α/β)8桶,而他们的底物特异性和抑制剂选择性取决于与残留位于三个高度外部循环变量。人类酶醛糖还原酶(AR或AKR1B1)因为AKR1B10生物医学的兴趣他们参与继发性糖尿病并发症(AR)和癌症。肝细胞癌和肺与吸烟有关癌症(AKR1B10)。AKRs与一系列的IC50值polyhalogenated化合物,2,2’,3、3 ',5,5 - 6、6标识为铅这两种酶的抑制剂用一个新的支架(1,1 ' -biphenyl-4 4 '二醇)。一个超高分辨率x射线结构AR-NADP + -JF0064复杂已经确定0.85 ?JF0064与催化残基通过一个带负电荷的羟基Tyr48(即酸性苯酚)。同时观察JF0064抑制模式酶表明这酸性羟基也出现在AKR1B10的情况。赖氨酸甲基化和表面的结合引入K125R, V301L突变启用了x射线的决心crystallo-graphic相应的结构AKR1B10-NADP + -JF0064复杂。两种结构揭示了一些重要线索为后续基于结构的药物设计的努力。

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