7b7v

Structure of NUDT15 in complex with Acyclovir monophosphate

spinqualitylabelsall models 7b7v, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7b7v is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.6Å Ligands: 4DG, CL, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NUD15_HUMAN Mediates the hydrolysis of some nucleoside diphosphate derivatives. Can degrade 8-oxo-dGTP in vitro, suggesting that it may remove an oxidatively damaged form of guanine (7,8-dihydro-8-oxoguanine) from DNA and the nucleotide pool, thereby preventing misincorporation of 8-oxo-dGTP into DNA thus preventing A:T to C:G transversions. Its substrate specificity in vivo however remains unclear (By similarity). May have a role in DNA synthesis and cell cycle progression through the interaction with PCNA. Publication Abstract from PubMed 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. NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir.,Nishii R, Mizuno T, Rehling D, Smith C, Clark BL, Zhao X, Brown SA, Smart B, Moriyama T, Yamada Y, Ichinohe T, Onizuka M, Atsuta Y, Yang L, Yang W, Thomas PG, Stenmark P, Kato M, Yang JJ Nat Commun. 2021 Jul 7;12(1):4181. doi: 10.1038/s41467-021-24509-7. PMID:34234136 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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