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The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1

Knecht, Kirsten M. ; Buzovetsky, Olga ; Schneider, Constanze ; Thomas, Dominique ; Srikanth, Vishok ; Kaderali, Lars ; Tofoleanu, Florentina ; Reiss, Krystle ; Ferreirós, Nerea ; Geisslinger, Gerd ; Batista, Victor S. ; Ji, Xiaoyun ; Cinatl, Jindrich ; Keppler, Oliver T. ; Xiong, Yong

Proceedings of the National Academy of Sciences - PNAS, 2018-10, Vol.115 (43), p.E10022-E10031 [Revista revisada por pares]

United States: National Academy of Sciences

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The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1
Autor: Knecht, Kirsten M. ; Buzovetsky, Olga ; Schneider, Constanze ; Thomas, Dominique ; Srikanth, Vishok ; Kaderali, Lars ; Tofoleanu, Florentina ; Reiss, Krystle ; Ferreirós, Nerea ; Geisslinger, Gerd ; Batista, Victor S. ; Ji, Xiaoyun ; Cinatl, Jindrich ; Keppler, Oliver T. ; Xiong, Yong
Materias: 60 APPLIED LIFE SCIENCES ; Acute myeloid leukemia ; Allosteric properties ; allosteric regulation ; Allosteric Site - drug effects ; Analogs ; Antineoplastic Agents - pharmacology ; Antiviral agents ; Biological Sciences ; Cancer ; Catalysis ; Catalytic Domain - drug effects ; Cell Line, Tumor ; Cellular structure ; Cladribine ; Crystallization ; Crystallography, X-Ray - methods ; Cytarabine ; dNTPase ; Drug Interactions - physiology ; Drugs ; Fludarabine ; Gemcitabine ; Genomes ; HL-60 Cells ; Humans ; Leukemia ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - metabolism ; Myeloid leukemia ; nucleotide analog drugs ; Nucleotide analogs ; Nucleotides ; Nucleotides - pharmacology ; Pharmacology ; PNAS Plus ; Ribonucleotide reductase ; SAM Domain and HD Domain-Containing Protein 1 - metabolism ; SAMHD1 ; substrate selection ; Substrate Specificity ; Substrates ; Sugar
Es parte de: Proceedings of the National Academy of Sciences - PNAS, 2018-10, Vol.115 (43), p.E10022-E10031
Notas: USDOE Office of Science (SC)
Yale Cancer Center
National Institutes of Health (NIH)
German Research Foundation (DFG)
National Science Foundation (NSF)
Hilfe für Krebskranke Kinder Frankfurt
Frankfurter Stiftung für Krebskranke Kinder
LOEWE-Center
National Institute of General Medical Sciences (NIGMS)
AI136737; AI120845; KE 742/4-1; T32 GM007223; DGE1122492; T32 GM008283; P41 GM103403; S10 RR029205; AC02-06CH11357
Author contributions: K.M.K., O.B., C.S., D.T., F.T., K.R., N.F., O.T.K., and Y.X. designed research; K.M.K., O.B., C.S., D.T., V.S., F.T., K.R., and N.F. performed research; K.M.K. and O.B. contributed new reagents/analytic tools; K.M.K., O.B., C.S., D.T., L.K., F.T., K.R., N.F., G.G., V.S.B., X.J., J.C., O.T.K., and Y.X. analyzed data; and K.M.K., O.B., and Y.X. wrote the paper
Edited by Celia A. Schiffer, University of Massachusetts Medical School, Worcester, MA, and accepted by Editorial Board Member Brenda A. Schulman September 6, 2018 (received for review April 2, 2018)
1K.M.K. and O.B. contributed equally to this work.
Descripción: 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.
Editor: United States: National Academy of Sciences
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The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1

Knecht, Kirsten M. ; Buzovetsky, Olga ; Schneider, Constanze ; Thomas, Dominique ; Srikanth, Vishok ; Kaderali, Lars ; Tofoleanu, Florentina ; Reiss, Krystle ; Ferreirós, Nerea ; Geisslinger, Gerd ; Batista, Victor S. ; Ji, Xiaoyun ; Cinatl, Jindrich ; Keppler, Oliver T. ; Xiong, Yong

United States: National Academy of Sciences

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