Thiopurine intolerance-causing mutations in NUDT15 induce temperature-dependent destabilization of the catalytic site

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F19%3A00503803" target="_blank" >RIV/61388963:_____/19:00503803 - isvavai.cz</a>
Alternative codes found
RIV/61388971:_____/19:00508147 RIV/68378050:_____/19:00508147 RIV/00216208:11310/19:10402857
Result on the web
<a href="https://www.sciencedirect.com/science/article/abs/pii/S1570963919300081?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/abs/pii/S1570963919300081?via%3Dihub</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.bbapap.2019.01.006" target="_blank" >10.1016/j.bbapap.2019.01.006</a>

Result language
angličtina
Original language name
Thiopurine intolerance-causing mutations in NUDT15 induce temperature-dependent destabilization of the catalytic site
Original language description
Germline mutations in NUDT15 cause thiopurine intolerance during treatment of leukemia or autoimmune diseases. Previously, it has been shown that the mutations affect the enzymatic activity of the NUDT15 hydrolase due to decreased protein stability in vivo. Here we provide structural insights into protein destabilization in R139C and V181 mutants using thermolysin-based proteolysis and H/D exchange followed by mass spectrometry. Both mutants exhibited destabilization of the catalytic site, which was more pronounced at higher temperature. This structural perturbation is shared by the mutations despite their different positions within the protein structure. Reaction products of NUDT15 reverted these conformational abnormalities, demonstrating the importance of ligands for stabilization of a native state of the mutants. This study shows the action of pharmacogenetic variants in NUDT15 in a context of protein structure, which might open novel directions in personalized chemotherapy.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology

Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2019
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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