7B7V

Structure of NUDT15 in complex with Acyclovir monophosphate

7B7V の概要

• エントリーDOI: 10.2210/pdb7b7v/pdb
• 分子名称: Probable 8-oxo-dGTP diphosphatase NUDT15, 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl dihydrogen phosphate, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: nucleoside triphosphate pyrophosphohydrolase, complex, antiviral hydrolase, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 38048.50

構造登録者

Rehling, D.,Stenmark, P. (登録日: 2020-12-11, 公開日: 2021-05-19, 最終更新日: 2024-01-31)

主引用文献

Nishii, R.,Mizuno, T.,Rehling, D.,Smith, C.,Clark, B.L.,Zhao, X.,Brown, S.A.,Smart, B.,Moriyama, T.,Yamada, Y.,Ichinohe, T.,Onizuka, M.,Atsuta, Y.,Yang, L.,Yang, W.,Thomas, P.G.,Stenmark, P.,Kato, M.,Yang, J.J.
NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir.
Nat Commun, 12:4181-4181, 2021

PubMed Abstract: Nucleobase and nucleoside analogs (NNA) are widely used as anti-viral and anti-cancer agents, and NNA phosphorylation is essential for the activity of this class of drugs. Recently, diphosphatase NUDT15 was linked to thiopurine metabolism with NUDT15 polymorphism associated with drug toxicity in patients. Profiling NNA drugs, we identify acyclovir (ACV) and ganciclovir (GCV) as two new NNAs metabolized by NUDT15. NUDT15 hydrolyzes ACV and GCV triphosphate metabolites, reducing their effects against cytomegalovirus (CMV) in vitro. Loss of NUDT15 potentiates cytotoxicity of ACV and GCV in host cells. In hematopoietic stem cell transplant patients, the risk of CMV viremia following ACV prophylaxis is associated with NUDT15 genotype (P = 0.015). Donor NUDT15 deficiency is linked to graft failure in patients receiving CMV-seropositive stem cells (P = 0.047). In conclusion, NUDT15 is an important metabolizing enzyme for ACV and GCV, and NUDT15 variation contributes to inter-patient variability in their therapeutic effects.

PubMed: 34234136
DOI: 10.1038/s41467-021-24509-7

実験手法

X-RAY DIFFRACTION (1.6 Å)