Small molecule inhibition of SAMHD1 dNTPase by tetramer destabilization.
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ABSTRACT:
SUBMITTER: Seamon KJ
PROVIDER: S-EPMC4105058 | biostudies-literature | 2014 Jul
REPOSITORIES: biostudies-literature
Publications
Small molecule inhibition of SAMHD1 dNTPase by tetramer destabilization.
Seamon Kyle J KJ Hansen Erik C EC Kadina Anastasia P AP Kashemirov Boris A BA McKenna Charles E CE Bumpus Namandjé N NN Stivers James T JT
Journal of the American Chemical Society 20140708 28
SAMHD1 is a GTP-activated nonspecific dNTP triphosphohydrolase that depletes dNTP pools in resting CD4+ T cells and macrophages and effectively restricts infection by HIV-1. We have designed a nonsubstrate dUTP analogue with a methylene bridge connecting the α phosphate and 5' carbon that potently inhibits SAMHD1. Although pppCH2dU shows apparent competitive inhibition, it acts by a surprising allosteric mechanism that destabilizes active enzyme tetramer. ...[more]
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