7AOM

Structure of NUDT15 in complex with Ganciclovir triphosphate

7AOM の概要

• エントリーDOI: 10.2210/pdb7aom/pdb
• 分子名称: Nucleotide triphosphate diphosphatase NUDT15, Ganciclovir triphosphate, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: nudix hydrolase, antiviral, 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: 38308.95

構造登録者

Rehling, D.,Zhang, S.M.,Helleday, T.,Stenmark, P. (登録日: 2020-10-14, 公開日: 2021-06-02, 最終更新日: 2024-01-31)

主引用文献

Zhang, S.M.,Rehling, D.,Jemth, A.S.,Throup, A.,Landazuri, N.,Almlof, I.,Gottmann, M.,Valerie, N.C.K.,Borhade, S.R.,Wakchaure, P.,Page, B.D.G.,Desroses, M.,Homan, E.J.,Scobie, M.,Rudd, S.G.,Berglund, U.W.,Soderberg-Naucler, C.,Stenmark, P.,Helleday, T.
NUDT15-mediated hydrolysis limits the efficacy of anti-HCMV drug ganciclovir.
Cell Chem Biol, 28:1693-1702.e6, 2021

PubMed Abstract: Ganciclovir (GCV) is the first-line therapy against human cytomegalovirus (HCMV), a widespread infection that is particularly dangerous for immunodeficient individuals. Closely resembling deoxyguanosine triphosphate, the tri-phosphorylated metabolite of GCV (GCV-TP) is preferentially incorporated by the viral DNA polymerase, thereby terminating chain extension and, eventually, viral replication. However, the treatment outcome of GCV varies greatly among individuals, therefore warranting better understanding of its metabolism. Here we show that NUDT15, a Nudix hydrolase known to metabolize thiopurine triphosphates, can similarly hydrolyze GCV-TP through biochemical studies and co-crystallization of the NUDT15/GCV-TP complex. More critically, GCV efficacy was potentiated in HCMV-infected cells following NUDT15 depletion by RNAi or inhibition by an in-house-developed, nanomolar NUDT15 inhibitor, TH8321, suggesting that pharmacological targeting of NUDT15 is a possible avenue to improve existing anti-HCMV regimens. Collectively, the data further implicate NUDT15 as a broad-spectrum metabolic regulator of nucleoside analog therapeutics, such as thiopurines and GCV.

PubMed: 34192523
DOI: 10.1016/j.chembiol.2021.06.001

実験手法

X-RAY DIFFRACTION (1.95 Å)