e99f570fbd68d9f4ab2dc4083d687fba pmc_34940623.pdf be2a01bb392f83887e637529f90608228fd41ef8 pmc_34940623.pdf 6195eaa3c14ac0f04b72a127a4169220c5ed64313da3cefa21aa004077884fdd pmc_34940623.pdf Title: Perspective on the Structural Basis for Human Aldo-Keto Reductase 1B10 Inhibition Subject: Human aldo-keto reductase 1B10 (AKR1B10) is overexpressed in many cancer types and is involved in chemoresistance. This makes AKR1B10 to be an interesting drug target and thus many enzyme inhibitors have been investigated. High-resolution crystallographic structures of AKR1B10 with various reversible inhibitors were deeply analyzed and compared to those of analogous complexes with aldose reductase (AR). In both enzymes, the active site included an anion-binding pocket and, in some cases, inhibitor binding caused the opening of a transient specificity pocket. Different structural conformers were revealed upon inhibitor binding, emphasizing the importance of the highly variable loops, which participate in the transient opening of additional binding subpockets. Two key differences between AKR1B10 and AR were observed regarding the role of external loops in inhibitor binding. The first corresponded to the alternative conformation of Trp112 (Trp111 in AR). The second difference dealt with loop A mobility, which defined a larger and more loosely packed subpocket in AKR1B10. From this analysis, the general features that a selective AKR1B10 inhibitor should comply with are the following: an anchoring moiety to the anion-binding pocket, keeping Trp112 in its native conformation (AKR1B10-like), and not opening the specificity pocket in AR. Keywords: aldo-keto reductase; aldose reductase; cancer; enzyme inhibitor; structure-based drug design Author: Francesc Xavier Ruiz, Xavier Parés and Jaume Farrés Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Dec 13 12:40:03 2021 CET ModDate: Mon Dec 13 12:45:23 2021 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 17 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 4602205 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- HKBJPQ+VnURWPalladioL Type 1 Custom yes yes no 10 0 MBMODF+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 MZBCWU+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 JYAJQI+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 BTFGED+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 ZZPUEX+ArialMT Type 1C WinAnsi yes yes no 37 0 TWGUDY+TimesNewRomanPS-BoldItalicMT Type 1C 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ArialMT CID TrueType Identity-H yes no yes 531 0 BCDEEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 554 0 BCDFEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 558 0 ArialMT CID TrueType Identity-H yes no yes 570 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-27 02:53:26 CEST RepresentationInformation: pmc_34940623.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 12:06:31 CEST Size: 4602205 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 871 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: AKR1B10 Inhibition Strategies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: AKR1B10 Reversible Inhibitors Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: AKR1B10 Covalent Inhibitors Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Potential for AKR1B10 Catalytic Activators Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: What We Have Learnt from 3D Structures Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Children: Item: Title: AKR1B10 Structure: Overview and Specific Features Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Structural Bases for AKR1B10 Selectivity Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Info: Title: Perspective on the Structural Basis for Human Aldo-Keto Reductase 1B10 Inhibition Author: Francesc Xavier Ruiz, Xavier Parés and Jaume Farrés Subject: Human aldo-keto reductase 1B10 (AKR1B10) is overexpressed in many cancer types and is involved in chemoresistance. This makes AKR1B10 to be an interesting drug target and thus many enzyme inhibitors have been investigated. High-resolution crystallographic structures of AKR1B10 with various reversible inhibitors were deeply analyzed and compared to those of analogous complexes with aldose reductase (AR). In both enzymes, the active site included an anion-binding pocket and, in some cases, inhibitor binding caused the opening of a transient specificity pocket. Different structural conformers were revealed upon inhibitor binding, emphasizing the importance of the highly variable loops, which participate in the transient opening of additional binding subpockets. Two key differences between AKR1B10 and AR were observed regarding the role of external loops in inhibitor binding. The first corresponded to the alternative conformation of Trp112 (Trp111 in AR). The second difference dealt with loop A mobility, which defined a larger and more loosely packed subpocket in AKR1B10. From this analysis, the general features that a selective AKR1B10 inhibitor should comply with are the following: an anchoring moiety to the anion-binding pocket, keeping Trp112 in its native conformation (AKR1B10-like), and not opening the specificity pocket in AR. 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