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

Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):E10022-E10031. doi: 10.1073/pnas.1805593115. Epub 2018 Oct 10.

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.

Keywords: SAMHD1; allosteric regulation; dNTPase; nucleotide analog drugs; substrate selection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Allosteric Site / drug effects*
  • Antineoplastic Agents / pharmacology
  • Catalytic Domain / drug effects*
  • Cell Line, Tumor
  • Crystallography, X-Ray / methods
  • Drug Interactions / physiology*
  • HL-60 Cells
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / metabolism*
  • Nucleotides / pharmacology
  • SAM Domain and HD Domain-Containing Protein 1 / metabolism*
  • Substrate Specificity

Substances

  • Antineoplastic Agents
  • Nucleotides
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human

Associated data

  • PDB/6DW4
  • PDB/6DWD
  • PDB/6DWK
  • PDB/6DW3
  • PDB/6DW5
  • PDB/6DW7