Molecular dynamics simulations reveal the impact of NUDT15 R139C and R139H variants in structural conformation and dynamics

NUDT15, also known as MTH2, is a member of the NUDIX protein family that catalyzes the hydrolysis of nucleotides and deoxynucleotides, as well as thioguanine analogues. NUDT15 has been reported as a DNA sanitizer in humans, and more recent studies have shown that some genetic variants are related to...

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Authors: Gómez Rubio, Elena, García Marin, Javier|||0000-0002-5883-4783
Format: article
Publication Date:2023
Country:España
Institution:Universidad de Alcalá (UAH)
Repository:e_Buah Biblioteca Digital Universidad de Alcalá
Language:English
OAI Identifier:oai:ebuah.uah.es:10017/60671
Online Access:http://hdl.handle.net/10017/60671
https://dx.doi.org/10.1080/07391102.2023.2187626
Access Level:Open access
Keyword:NUDT15
MTH2
nudix hydrolase
molecular dynamics
thiopurine
PCA
Química
Chemistry
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spelling Molecular dynamics simulations reveal the impact of NUDT15 R139C and R139H variants in structural conformation and dynamicsGómez Rubio, ElenaGarcía Marin, Javier|||0000-0002-5883-4783NUDT15MTH2nudix hydrolasemolecular dynamicsthiopurinePCAQuímicaChemistryNUDT15, also known as MTH2, is a member of the NUDIX protein family that catalyzes the hydrolysis of nucleotides and deoxynucleotides, as well as thioguanine analogues. NUDT15 has been reported as a DNA sanitizer in humans, and more recent studies have shown that some genetic variants are related to a poor prognosis in neoplastic and immunologic diseases treated with thioguanine drugs. Despite this, the role of NUDT15 in physiology and molecular biology is quite unclear, as is the mechanism of action of this enzyme. The existence of clinically relevant variants has prompted the study of these enzymes, whose capacity to bind and hydrolyze thioguanine nucleotides is still poorly understood. By using a combination of biomolecular modeling techniques and molecular dynamics, we have studied the monomeric wild type NUDT15 as well as two important variants, R139C and R139H. Our findings reveal not only how nucleotide binding stabilizes the enzyme but also how two loops are responsible for keeping the enzyme in a packed, close conformation. Mutations in ?2 helix affect a network of hydrophobic and ?-interactions that enclose the active site. This knowledge contributes to the understanding of NUDT15 structural dynamics and will be valuable for the design of new chemical probes and drugs targeting this protein.20232023-03-1220232023-03-1220242024-03-12journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10017/60671https://dx.doi.org/10.1080/07391102.2023.2187626reponame:e_Buah Biblioteca Digital Universidad de Alcaláinstname:Universidad de Alcalá (UAH)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:ebuah.uah.es:10017/606712026-06-18T11:13:07Z
dc.title.none.fl_str_mv Molecular dynamics simulations reveal the impact of NUDT15 R139C and R139H variants in structural conformation and dynamics
title Molecular dynamics simulations reveal the impact of NUDT15 R139C and R139H variants in structural conformation and dynamics
spellingShingle Molecular dynamics simulations reveal the impact of NUDT15 R139C and R139H variants in structural conformation and dynamics
Gómez Rubio, Elena
NUDT15
MTH2
nudix hydrolase
molecular dynamics
thiopurine
PCA
Química
Chemistry
title_short Molecular dynamics simulations reveal the impact of NUDT15 R139C and R139H variants in structural conformation and dynamics
title_full Molecular dynamics simulations reveal the impact of NUDT15 R139C and R139H variants in structural conformation and dynamics
title_fullStr Molecular dynamics simulations reveal the impact of NUDT15 R139C and R139H variants in structural conformation and dynamics
title_full_unstemmed Molecular dynamics simulations reveal the impact of NUDT15 R139C and R139H variants in structural conformation and dynamics
title_sort Molecular dynamics simulations reveal the impact of NUDT15 R139C and R139H variants in structural conformation and dynamics
dc.creator.none.fl_str_mv Gómez Rubio, Elena
García Marin, Javier|||0000-0002-5883-4783
author Gómez Rubio, Elena
author_facet Gómez Rubio, Elena
García Marin, Javier|||0000-0002-5883-4783
author_role author
author2 García Marin, Javier|||0000-0002-5883-4783
author2_role author
dc.subject.none.fl_str_mv NUDT15
MTH2
nudix hydrolase
molecular dynamics
thiopurine
PCA
Química
Chemistry
topic NUDT15
MTH2
nudix hydrolase
molecular dynamics
thiopurine
PCA
Química
Chemistry
description NUDT15, also known as MTH2, is a member of the NUDIX protein family that catalyzes the hydrolysis of nucleotides and deoxynucleotides, as well as thioguanine analogues. NUDT15 has been reported as a DNA sanitizer in humans, and more recent studies have shown that some genetic variants are related to a poor prognosis in neoplastic and immunologic diseases treated with thioguanine drugs. Despite this, the role of NUDT15 in physiology and molecular biology is quite unclear, as is the mechanism of action of this enzyme. The existence of clinically relevant variants has prompted the study of these enzymes, whose capacity to bind and hydrolyze thioguanine nucleotides is still poorly understood. By using a combination of biomolecular modeling techniques and molecular dynamics, we have studied the monomeric wild type NUDT15 as well as two important variants, R139C and R139H. Our findings reveal not only how nucleotide binding stabilizes the enzyme but also how two loops are responsible for keeping the enzyme in a packed, close conformation. Mutations in ?2 helix affect a network of hydrophobic and ?-interactions that enclose the active site. This knowledge contributes to the understanding of NUDT15 structural dynamics and will be valuable for the design of new chemical probes and drugs targeting this protein.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-03-12
2023
2023-03-12
2024
2024-03-12
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10017/60671
https://dx.doi.org/10.1080/07391102.2023.2187626
url http://hdl.handle.net/10017/60671
https://dx.doi.org/10.1080/07391102.2023.2187626
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/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
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:e_Buah Biblioteca Digital Universidad de Alcalá
instname:Universidad de Alcalá (UAH)
instname_str Universidad de Alcalá (UAH)
reponame_str e_Buah Biblioteca Digital Universidad de Alcalá
collection e_Buah Biblioteca Digital Universidad de Alcalá
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