In vitro inhibition of AKR1Cs by sulphonylureas and the structural basis

Zhao, Yiting; Zheng, Xuehua; Zhang, Hong; Zhai, Jing; Zhang, Liping; Li, Cuiyun; Zeng, Kaixin; Chen, Yunyun; Li, Qing; Hu, Xiaopeng

doi:10.1016/j.cbi.2015.09.006

Cited by 39 publications

(31 citation statements)

References 36 publications

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“…S4C-S4E). The extended conformation of GBM bound to SUR1 is dramatically different from the compact conformation of GBM bound to human aldo-keto reductase 1C3 subfamily (AKR1Cs) (Zhao et al, 2015) (Fig. S4C).…”

Section: Gbm Binding Site On Sur1mentioning

confidence: 94%

Ligand binding and conformational changes of SUR1 subunit in pancreatic ATP-sensitive potassium channels

Ding

Wang

et al. 2018

Preprint

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ATP-sensitive potassium channels (K ATP ) are energy sensors on the plasma membrane. By sensing the intracellular ADP/ATP ratio of β-cells, pancreatic K ATP channels control insulin release and regulate metabolism at the whole body level. They are implicated in many metabolic disorders and diseases and are therefore important drug targets. Here, we present three structures of pancreatic K ATP channels solved by cryo-electron microscopy (cryo-EM), at resolutions ranging from 4.1 to 4.5 Å. These structures depict the binding site of the antidiabetic drug glibenclamide, indicate how Kir6.2 N-terminus participates the coupling between the peripheral SUR1 subunit and the central Kir6.2 channel, reveal the binding mode of activating nucleotides, and suggest the mechanism of how Mg-ADP binding on nucleotide binding domains (NBDs) drives a conformational change of the SUR1 subunit.

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Section: Gbm Binding Site On Sur1mentioning

confidence: 94%

Ligand binding and conformational changes of SUR1 subunit in pancreatic ATP-sensitive potassium channels

Ding

Wang

et al. 2018

Preprint

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“…AKR1C3 is inhibited by several classes of AKR1C3 inhibitors, including cinnamic acid (Brozic et al, 2006a), non-steroidal anti-inflammatory drugs (NSAIDs) and their derivatives (Gobec et al, 2005; Byrns et al, 2008; Liedtke et al, 2013), steroid hormone analoges (Bydal et al, 2009), flavonoids (Skarydova et al, 2009), cyclopentanes (Stefane et al, 2009), benzoic acids (Adeniji et al, 2011; Jamieson et al, 2012), progestins (Beranic et al, 2011), baccharin analogs (Zang et al, 2015), ruthenium complexes (Kljun et al, 2016), and the most widely used anti-diabetes drugs, sulfonylureas (Zhao et al, 2015). Most inhibitors of AKR1C3 are carboxylic acids, whose transport into cells is likely dominated by carrier-mediated processes.…”

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Aldo–Keto Reductase AKR1C1–AKR1C4: Functions, Regulation, and Intervention for Anti-cancer Therapy

et al. 2017

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Aldo–keto reductases comprise of AKR1C1–AKR1C4, four enzymes that catalyze NADPH dependent reductions and have been implicated in biosynthesis, intermediary metabolism, and detoxification. Recent studies have provided evidences of strong correlation between the expression levels of these family members and the malignant transformation as well as the resistance to cancer therapy. Mechanistically, most studies focus on the catalytic-dependent function of AKR1C isoforms, like their impeccable roles in prostate cancer, breast cancer, and drug resistance due to the broad substrates specificity. However, accumulating clues showed that catalytic-independent functions also played critical roles in regulating biological events. This review summarizes the catalytic-dependent and -independent roles of AKR1Cs, as well as the small molecule inhibitors targeting these family members.

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“…In previous reports, AKR1C3 constructs with an N-terminal His tag were routinely used for enzymatic assays, while structural analyses were performed using constructs with a C-terminal His tag (Jamieson et al, 2012). Only three of the 43 AKR1C3 structures in the PDB were determined using a construct with an N-terminal His tag, with resolutions of 2.0 and 2.3 Å (Zhao et al, 2015), while 29 of the AKR1C3 structures were solved using a C-terminally His-tagged construct, with resolutions ranging from 1.2 Å , which was the best resolution achieved for AKR1C3 (Lovering et al, 2004), to 2.8 Å , with an average resolution of 1.9 Å . Three AKR1C3 structures were solved from a GST-fusion construct, where the GST was removed before crystallization (Qiu et al, 2004(Qiu et al, , 2007, and the remaining structures originated from untagged protein.…”

Section: Resultsmentioning

confidence: 99%

“…However, by far the vast majority of AKR1C3 structures reported used a noncleavable histidine tag (His 6 ) at the C-terminus of the protein (Flanagan et al, 2012(Flanagan et al, , 2014Jackson et al, 2012;Jamieson et al, 2012;Heinrich et al, 2013;Amano et al, 2015). Several AKR1C3 structures with an uncleaved N-terminal His 6 tag have also been determined recently (Zhao et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

In situproteolysis of an N-terminal His tag with thrombin improves the diffraction quality of human aldo-keto reductase 1C3 crystals

et al. 2018

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Human aldo-keto reductase 1C3 (AKR1C3) stereospecifically reduces steroids and prostaglandins and is involved in the biotransformation of xenobiotics. Its role in various cancers makes it a potential therapeutic target for the development of inhibitors. Recombinant AKR1C3 with a thrombin-cleavable N-terminal His tag was expressed from a pET-28(+) vector for structural studies of enzyme-inhibitor complexes. A modified in situ proteolysis approach was applied to specifically remove the His tag by thrombin cleavage during crystallization screening trials. This improved the morphology and diffraction quality of the crystals and allowed the acquisition of high-resolution diffraction data and structure solution. This approach may be generally applicable to other proteins expressed using the pET-28(+) vector.

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In vitro inhibition of AKR1Cs by sulphonylureas and the structural basis

Cited by 39 publications

References 36 publications

Ligand binding and conformational changes of SUR1 subunit in pancreatic ATP-sensitive potassium channels

Ligand binding and conformational changes of SUR1 subunit in pancreatic ATP-sensitive potassium channels

Aldo–Keto Reductase AKR1C1–AKR1C4: Functions, Regulation, and Intervention for Anti-cancer Therapy

In situproteolysis of an N-terminal His tag with thrombin improves the diffraction quality of human aldo-keto reductase 1C3 crystals

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