6CM2

SAMHD1 HD domain bound to decitabine triphosphate

6CM2 の概要

• エントリーDOI: 10.2210/pdb6cm2/pdb
• 分子名称: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1, 6-amino-3-{2-deoxy-5-O-[(R)-hydroxy{[(S)-hydroxy(phosphonooxy)phosphoryl]oxy}phosphoryl]-beta-D-erythro-pentofuranosyl}-3,4-dihydro-1,3,5-triazin-2(1H)-one, GUANOSINE-5'-TRIPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: samhd1, analogues, decitabine, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 244367.92

構造登録者

Oellerich, T.,Schneider, C.,Thomas, D.,Knecht, K.M.,Buzovetsky, O.,Kaderali, L.,Schliemann, C.,Bohnenberger, H.,Angenendt, L.,Hartmann, W.,Wardelmann, E.,Rothenburger, T.,Mohr, S.,Scheich, S.,Comoglio, F.,Wilke, A.,Strobel, P.,Serve, H.,Michaelis, M.,Ferreiros, N.,Geisslinger, G.,Xiong, Y.,Keppler, O.T.,Cinatl, J. (登録日: 2018-03-02, 公開日: 2019-06-19, 最終更新日: 2023-10-04)

主引用文献

Oellerich, T.,Schneider, C.,Thomas, D.,Knecht, K.M.,Buzovetsky, O.,Kaderali, L.,Schliemann, C.,Bohnenberger, H.,Angenendt, L.,Hartmann, W.,Wardelmann, E.,Rothenburger, T.,Mohr, S.,Scheich, S.,Comoglio, F.,Wilke, A.,Strobel, P.,Serve, H.,Michaelis, M.,Ferreiros, N.,Geisslinger, G.,Xiong, Y.,Keppler, O.T.,Cinatl Jr., J.
Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML.
Nat Commun, 10:3475-3475, 2019

PubMed Abstract: Hypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms of action remain incompletely understood, and predictive biomarkers for HMA efficacy are lacking. Here, we show that the bioactive metabolite decitabine triphosphate, but not azacytidine triphosphate, functions as activator and substrate of the triphosphohydrolase SAMHD1 and is subject to SAMHD1-mediated inactivation. Retrospective immunohistochemical analysis of bone marrow specimens from AML patients at diagnosis revealed that SAMHD1 expression in leukemic cells inversely correlates with clinical response to decitabine, but not to azacytidine. SAMHD1 ablation increases the antileukemic activity of decitabine in AML cell lines, primary leukemic blasts, and xenograft models. AML cells acquire resistance to decitabine partly by SAMHD1 up-regulation. Together, our data suggest that SAMHD1 is a biomarker for the stratified use of hypomethylating agents in AML patients and a potential target for the treatment of decitabine-resistant leukemia.

PubMed: 31375673
DOI: 10.1038/s41467-019-11413-4

実験手法

X-RAY DIFFRACTION (2.14 Å)