6DW3

SAMHD1 Bound to Cytarabine-TP in the Catalytic Pocket

6DW3 の概要

• エントリーDOI: 10.2210/pdb6dw3/pdb
• 分子名称: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1, 4-amino-1-{5-O-[(S)-hydroxy{[(R)-hydroxy(phosphonooxy)phosphoryl]oxy}phosphoryl]-beta-D-arabinofuranosyl}pyrimidin-2(1H)-one, 2'-DEOXYADENOSINE 5'-TRIPHOSPHATE, ... (6 entities in total)
• 機能のキーワード: complex, deoxynucleoside triphosphate triphosphohydrolase, dntpase, nucleotide analogue, cytarabine-tp, hydrolase, hydrolase inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 259890.01

構造登録者

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. (登録日: 2018-06-26, 公開日: 2018-10-10, 最終更新日: 2023-10-11)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.2 Å)