Perspective on the Structural Basis for Human Aldo-Keto Reductase 1B10 Inhibition
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 reversibl...
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| Format: | Article |
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MDPI AG
2021-12-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/11/12/865 |
| _version_ | 1797502497382727680 |
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| author | Francesc Xavier Ruiz Xavier Parés Jaume Farrés |
| author_facet | Francesc Xavier Ruiz Xavier Parés Jaume Farrés |
| author_sort | Francesc Xavier Ruiz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T03:34:55Z |
| format | Article |
| id | doaj.art-1f27dd42c0774a4f89ac513747b77905 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-10T03:34:55Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-1f27dd42c0774a4f89ac513747b779052023-11-23T09:32:00ZengMDPI AGMetabolites2218-19892021-12-01111286510.3390/metabo11120865Perspective on the Structural Basis for Human Aldo-Keto Reductase 1B10 InhibitionFrancesc Xavier Ruiz0Xavier Parés1Jaume Farrés2Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USADepartment of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Bellaterra, E-08193 Barcelona, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Bellaterra, E-08193 Barcelona, SpainHuman 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.https://www.mdpi.com/2218-1989/11/12/865aldo-keto reductasealdose reductasecancerenzyme inhibitorstructure-based drug design |
| spellingShingle | Francesc Xavier Ruiz Xavier Parés Jaume Farrés Perspective on the Structural Basis for Human Aldo-Keto Reductase 1B10 Inhibition Metabolites aldo-keto reductase aldose reductase cancer enzyme inhibitor structure-based drug design |
| title | Perspective on the Structural Basis for Human Aldo-Keto Reductase 1B10 Inhibition |
| title_full | Perspective on the Structural Basis for Human Aldo-Keto Reductase 1B10 Inhibition |
| title_fullStr | Perspective on the Structural Basis for Human Aldo-Keto Reductase 1B10 Inhibition |
| title_full_unstemmed | Perspective on the Structural Basis for Human Aldo-Keto Reductase 1B10 Inhibition |
| title_short | Perspective on the Structural Basis for Human Aldo-Keto Reductase 1B10 Inhibition |
| title_sort | perspective on the structural basis for human aldo keto reductase 1b10 inhibition |
| topic | aldo-keto reductase aldose reductase cancer enzyme inhibitor structure-based drug design |
| url | https://www.mdpi.com/2218-1989/11/12/865 |
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