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Crystal structures ...
Crystal structures of NUDT15 variants enabled by a potent inhibitor reveal the structural basis for thiopurine sensitivity
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- Rehling, Daniel (author)
- Stockholm University,Stockholms universitet,Institutionen för biokemi och biofysik
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- Zhang, Si Min (author)
- Karolinska Institutet,Karolinska Institute
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- Jemth, Ann-Sofie (author)
- Karolinska Institutet
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show more...
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- Koolmeister, Tobias (author)
- Karolinska Institutet
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Throup, Adam (author)
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- Wallner, Olov (author)
- Karolinska Institutet
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- Scaletti, Emma (author)
- Stockholm 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
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- Moriyama, Takaya (author)
- St Jude Children´s Research Hospital, Memphis
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- Nishii, Rina (author)
- St Jude Children´s Research Hospital, Memphis
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- Davies, Jonathan (author)
- Stockholm University,Stockholms universitet,Institutionen för biokemi och biofysik,Lund University, Sweden
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Desroses, Matthieu (author)
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- Rudd, Sean G. (author)
- Karolinska Institutet
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- Scobie, Martin (author)
- Karolinska Institutet
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- Homan, Evert (author)
- Karolinska Institutet
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- Warpman Berglund, Ulrika (author)
- Karolinska Institutet
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- Yang, Jun J. (author)
- St Jude Children´s Research Hospital, Memphis
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- Helleday, Thomas (author)
- Karolinska Institutet
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- Stenmark, Pål (author)
- Stockholm 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
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(creator_code:org_t)
- Elsevier BV, 2021
- 2021
- English.
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In: Journal of Biological Chemistry. - : Elsevier BV. - 0021-9258 .- 1083-351X. ; 296
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Abstract
Subject headings
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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
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- NATURVETENSKAP -- Biologi -- Strukturbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Structural Biology (hsv//eng)
Keyword
- NUDT15
- NUDIX
- hydrolase
- MTH2
- inhibitor
- crystal structure
- Biochemistry
- biokemi
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Rehling, Daniel
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Zhang, Si Min
-
Jemth, Ann-Sofie
-
Koolmeister, Tob ...
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Throup, Adam
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Wallner, Olov
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show more...
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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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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmacology and ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Structural Biolo ...
- Articles in the publication
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Journal of Biolo ...
- By the university
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Stockholm University
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Lund University
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Karolinska Institutet