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Crystal structures ...
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Rehling, DanielStockholm University,Stockholms universitet,Institutionen för biokemi och biofysik
(author)
Crystal structures of NUDT15 variants enabled by a potent inhibitor reveal the structural basis for thiopurine sensitivity
- Article/chapterEnglish2021
Publisher, publication year, extent ...
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Elsevier BV,2021
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printrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:su-195219
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https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-195219URI
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https://doi.org/10.1016/j.jbc.2021.100568DOI
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https://lup.lub.lu.se/record/8780462f-c9d4-451d-aa12-c4aaa707f667URI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:147392923URI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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The enzyme NUDT15 efficiently hydrolyzes the active metabolites of thiopurine drugs, which are routinely used for treating cancer and inflammatory diseases. Loss-of-function variants in NUDT15 are strongly associated with thiopurine intolerance, such as leukopenia, and preemptive NUDT15 genotyping has been clinically implemented to personalize thiopurine dosing. However, understanding the molecular consequences of these variants has been difficult, as no structural information was available for NUDT15 proteins encoded by clinically actionable pharmacogenetic variants because of their inherent instability. Recently, the small molecule NUDT15 inhibitor TH1760 has been shown to sensitize cells to thiopurines, through enhanced accumulation of 6-thio-guanine in DNA. Building upon this, we herein report the development of the potent and specific NUDT15 inhibitor, TH7755. TH7755 demonstrates a greatly improved cellular target engagement and 6-thioguanine potentiation compared with TH1760, while showing no cytotoxicity on its own. This potent inhibitor also stabilized NUDT15, enabling analysis by X-ray crystallography. We have determined high-resolution structures of the clinically relevant NUDT15 variants Arg139Cys, Arg139His, Val18Ile, and V18_V19insGlyVal. These structures provide clear insights into the structural basis for the thiopurine intolerance phenotype observed in patients carrying these pharmacogenetic variants. These findings will aid in predicting the effects of new NUDT15 sequence variations yet to be discovered in the clinic.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Zhang, Si MinKarolinska Institutet,Karolinska Institute
(author)
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Jemth, Ann-SofieKarolinska Institutet
(author)
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Koolmeister, TobiasKarolinska Institutet
(author)
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Throup, Adam
(author)
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Wallner, OlovKarolinska Institutet
(author)
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Scaletti, EmmaStockholm University,Lunds universitet,Stockholms universitet,Institutionen för biokemi och biofysik,Lund University, Sweden,Strukturell biokemi,Forskargrupper vid Lunds universitet,Structural Biochemistry,Lund University Research Groups(Swepub:lu)em4772sc
(author)
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Moriyama, TakayaSt Jude Children´s Research Hospital, Memphis
(author)
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Nishii, RinaSt Jude Children´s Research Hospital, Memphis
(author)
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Davies, JonathanStockholm University,Stockholms universitet,Institutionen för biokemi och biofysik,Lund University, Sweden(Swepub:su)joda5966
(author)
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Desroses, Matthieu
(author)
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Rudd, Sean G.Karolinska Institutet
(author)
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Scobie, MartinKarolinska Institutet
(author)
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Homan, EvertKarolinska Institutet
(author)
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Warpman Berglund, UlrikaKarolinska Institutet
(author)
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Yang, Jun J.St Jude Children´s Research Hospital, Memphis
(author)
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Helleday, ThomasKarolinska Institutet
(author)
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Stenmark, PålStockholm University,Lunds universitet,Stockholms universitet,Institutionen för biokemi och biofysik,Lund University, Sweden,Strukturell biokemi,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Structural Biochemistry,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments(Swepub:lu)pa4463st
(author)
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Stockholms universitetInstitutionen för biokemi och biofysik
(creator_code:org_t)
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In:Journal of Biological Chemistry: Elsevier BV2960021-92581083-351X
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Rehling, Daniel
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Zhang, Si Min
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Jemth, Ann-Sofie
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Koolmeister, Tob ...
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Throup, Adam
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Wallner, Olov
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Scaletti, Emma
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Moriyama, Takaya
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Nishii, Rina
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Davies, Jonathan
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Desroses, Matthi ...
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Rudd, Sean G.
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Scobie, Martin
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Homan, Evert
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Warpman Berglund ...
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Yang, Jun J.
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Helleday, Thomas
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Stenmark, Pål
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Stockholm University
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Karolinska Institutet