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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Autores: Ruiz, Francesc Xavier|||0000-0002-0457-0030, Parés i Casasampera, Xavier|||0000-0002-5071-9465, Farrés, Jaume|||0000-0001-9069-3987
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:255900
Acceso en línea:https://ddd.uab.cat/record/255900
https://dx.doi.org/urn:doi:10.3390/metabo11120865
Access Level:acceso abierto
Palabra clave:Aldo-keto reductase
Aldose reductase
Cancer
Enzyme inhibitor
Structure-based drug design
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spelling Perspective on the structural basis for human aldo-keto reductase 1b10 inhibitionRuiz, Francesc Xavier|||0000-0002-0457-0030Parés i Casasampera, Xavier|||0000-0002-5071-9465Farrés, Jaume|||0000-0001-9069-3987Aldo-keto reductaseAldose reductaseCancerEnzyme inhibitorStructure-based drug designHuman 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. 22021-01-0120212021-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/255900https://dx.doi.org/urn:doi:10.3390/metabo11120865reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2020-119424RB-I00open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2559002026-06-06T12:50:31Z
dc.title.none.fl_str_mv Perspective on the structural basis for human aldo-keto reductase 1b10 inhibition
title Perspective on the structural basis for human aldo-keto reductase 1b10 inhibition
spellingShingle Perspective on the structural basis for human aldo-keto reductase 1b10 inhibition
Ruiz, Francesc Xavier|||0000-0002-0457-0030
Aldo-keto reductase
Aldose reductase
Cancer
Enzyme inhibitor
Structure-based drug design
title_short 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_sort Perspective on the structural basis for human aldo-keto reductase 1b10 inhibition
dc.creator.none.fl_str_mv Ruiz, Francesc Xavier|||0000-0002-0457-0030
Parés i Casasampera, Xavier|||0000-0002-5071-9465
Farrés, Jaume|||0000-0001-9069-3987
author Ruiz, Francesc Xavier|||0000-0002-0457-0030
author_facet Ruiz, Francesc Xavier|||0000-0002-0457-0030
Parés i Casasampera, Xavier|||0000-0002-5071-9465
Farrés, Jaume|||0000-0001-9069-3987
author_role author
author2 Parés i Casasampera, Xavier|||0000-0002-5071-9465
Farrés, Jaume|||0000-0001-9069-3987
author2_role author
author
dc.subject.none.fl_str_mv Aldo-keto reductase
Aldose reductase
Cancer
Enzyme inhibitor
Structure-based drug design
topic Aldo-keto reductase
Aldose reductase
Cancer
Enzyme inhibitor
Structure-based drug design
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.
publishDate 2021
dc.date.none.fl_str_mv 2
2021-01-01
2021
2021-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/255900
https://dx.doi.org/urn:doi:10.3390/metabo11120865
url https://ddd.uab.cat/record/255900
https://dx.doi.org/urn:doi:10.3390/metabo11120865
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2020-119424RB-I00
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
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repository.mail.fl_str_mv
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