7AOM
Structure of NUDT15 in complex with Ganciclovir triphosphate
Summary for 7AOM
| Entry DOI | 10.2210/pdb7aom/pdb |
| Descriptor | Nucleotide triphosphate diphosphatase NUDT15, Ganciclovir triphosphate, MAGNESIUM ION, ... (4 entities in total) |
| Functional Keywords | nudix hydrolase, antiviral, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 38308.95 |
| Authors | Rehling, D.,Zhang, S.M.,Helleday, T.,Stenmark, P. (deposition date: 2020-10-14, release date: 2021-06-02, Last modification date: 2024-01-31) |
| Primary citation | 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 Cited by 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: 34192523DOI: 10.1016/j.chembiol.2021.06.001 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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