2021
DOI: 10.1016/j.jbc.2021.100568
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Crystal structures of NUDT15 variants enabled by a potent inhibitor reveal the structural basis for thiopurine sensitivity

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Cited by 10 publications
(18 citation statements)
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“…NUDT15 deactivates the nucleoside analog antimetabolite, thiopurine, by hydrolyzing the active triphosphates and limiting DNA damage-induced toxicity 16, 28 . Several destabilizing variants of NUDT15 have been associated with clinical thiopurine intolerance 28 and can be stabilized towards thermal denaturation by NUDT15 inhibitors (NUDT15i) in vitro 29 , including R139C, which is known to be rapidly degraded by the proteasome 16 . When cells expressing an HA-tagged R139C variant were incubated with thioguanine, we saw increased incorporation-related DNA damage but, interestingly, also an accumulation of HA-R139C ( Fig.…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…NUDT15 deactivates the nucleoside analog antimetabolite, thiopurine, by hydrolyzing the active triphosphates and limiting DNA damage-induced toxicity 16, 28 . Several destabilizing variants of NUDT15 have been associated with clinical thiopurine intolerance 28 and can be stabilized towards thermal denaturation by NUDT15 inhibitors (NUDT15i) in vitro 29 , including R139C, which is known to be rapidly degraded by the proteasome 16 . When cells expressing an HA-tagged R139C variant were incubated with thioguanine, we saw increased incorporation-related DNA damage but, interestingly, also an accumulation of HA-R139C ( Fig.…”
Section: Resultsmentioning
confidence: 99%
“…3c). An enzymecoupled malachite green inhibition assay determined that NSC56456 and TH8234 similarly inhibited dGTP hydrolysis (IC50 = 355 and 375 nM, respectively), albeit less potently than optimized NUDT15i [29][30][31] , while TH8228 was completely inactive (Fig. 3d).…”
Section: Illuminating Complex Nudt15-thiopurine Interactions With The...mentioning
confidence: 96%
“…Among the different NUTD15 variants identified up to date, we selected for our purposes two well characterized mutants, both with substitutions in the position of Arg139 by a cysteine (R139C) and histidine (R139H). This decision was based in the clinical relevance of these mutants in thiopurine therapy and the availability of experimental data to validate and compare our computational results (Table 1) (Yang and others 2014; Rehling and others 2021; Cargnin and others 2018).…”
Section: Resultsmentioning
confidence: 99%
“…NUDIXs substrate specificity has been the object of extensive research, and recent studies have proved that NUTD15 is able to hydrolyze metabolites of thiopurines drugs like 6-thio-deoxyguanosine triphosphate (Rehling and others 2021; Valerie and others 2016). Azathioprine, mercaptopurine and thioguanine belong to the group of thiopurine antimetabolites, a kind of drugs that, after their bioactivation inside the cell into thioguanosine triphosphate (TGTP), inhibit several enzymes belonging to the purine biosynthesis and produce misincorporation into DNA and RNA (Figure 1) (Karran and Attard 2008).…”
Section: Introductionmentioning
confidence: 99%
“…While polymorphisms in TPMT alone explain around 40% of thiopurine-induced ADRs (Schaeffeler et al 2019 ), predictions can be further improved by including the missense variant p.R139C in NUDT15 (c.415C > T; rs116855232) (Yang et al 2015b , 2014 ). Mechanistically, this variant destabilizes the protein structure, thereby resulting in lower enzymatic activity (Rehling et al 2021 ). p.R139C defines NUDT15*3 and is moreover part of NUDT15*2 in combination with the inframe deletion variant (rs746071566), in both cases resulting in a loss of gene product function.…”
Section: Tpmt and Nudt15mentioning
confidence: 99%