6CM2

SAMHD1 HD domain bound to decitabine triphosphate

Summary for 6CM2

• Entry DOI: 10.2210/pdb6cm2/pdb
• Descriptor: 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)
• Functional Keywords: samhd1, analogues, decitabine, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 244367.92

Authors

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. (deposition date: 2018-03-02, release date: 2019-06-19, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.14 Å)