7B7V

Structure of NUDT15 in complex with Acyclovir monophosphate

Summary for 7B7V

• Entry DOI: 10.2210/pdb7b7v/pdb
• Descriptor: 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)
• Functional Keywords: nucleoside triphosphate pyrophosphohydrolase, complex, antiviral hydrolase, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 38048.50

Authors

Rehling, D.,Stenmark, P. (deposition date: 2020-12-11, release date: 2021-05-19, Last modification date: 2024-01-31)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.6 Å)