6DW5

SAMHD1 Bound to Gemcitabine-TP in the Catalytic Pocket

Summary for 6DW5

• Entry DOI: 10.2210/pdb6dw5/pdb
• Descriptor: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1, 2'-deoxy-2',2'-difluorocytidine 5'-(tetrahydrogen triphosphate), GUANOSINE-5'-TRIPHOSPHATE, ... (8 entities in total)
• Functional Keywords: complex, deoxynucleoside triphosphate triphosphohydrolase, dntpase, nucleotide analogue, gemcitabine-tp, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 260169.20

Authors

Knecht, K.M.,Buzovetsky, O.,Schneider, C.,Thomas, D.,Srikanth, V.,Kaderali, L.,Tofoleanu, F.,Reiss, K.,Ferreiros, N.,Geisslinger, G.,Batista, V.S.,Ji, X.,Cinatl, J.,Keppler, O.T.,Xiong, Y. (deposition date: 2018-06-26, release date: 2018-10-10, Last modification date: 2024-03-13)

Primary citation

Knecht, K.M.,Buzovetsky, O.,Schneider, C.,Thomas, D.,Srikanth, V.,Kaderali, L.,Tofoleanu, F.,Reiss, K.,Ferreiros, N.,Geisslinger, G.,Batista, V.S.,Ji, X.,Cinatl Jr., J.,Keppler, O.T.,Xiong, Y.
The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1.
Proc. Natl. Acad. Sci. U.S.A., 115:E10022-E10031, 2018

PubMed Abstract: SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that depletes cellular dNTPs in noncycling cells to promote genome stability and to inhibit retroviral and herpes viral replication. In addition to being substrates, cellular nucleotides also allosterically regulate SAMHD1 activity. Recently, it was shown that high expression levels of SAMHD1 are also correlated with significantly worse patient responses to nucleotide analog drugs important for treating a variety of cancers, including acute myeloid leukemia (AML). In this study, we used biochemical, structural, and cellular methods to examine the interactions of various cancer drugs with SAMHD1. We found that both the catalytic and the allosteric sites of SAMHD1 are sensitive to sugar modifications of the nucleotide analogs, with the allosteric site being significantly more restrictive. We crystallized cladribine-TP, clofarabine-TP, fludarabine-TP, vidarabine-TP, cytarabine-TP, and gemcitabine-TP in the catalytic pocket of SAMHD1. We found that all of these drugs are substrates of SAMHD1 and that the efficacy of most of these drugs is affected by SAMHD1 activity. Of the nucleotide analogs tested, only cladribine-TP with a deoxyribose sugar efficiently induced the catalytically active SAMHD1 tetramer. Together, these results establish a detailed framework for understanding the substrate specificity and allosteric activation of SAMHD1 with regard to nucleotide analogs, which can be used to improve current cancer and antiviral therapies.

PubMed: 30305425
DOI: 10.1073/pnas.1805593115

Experimental method

X-RAY DIFFRACTION (1.93 Å)