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Small molecule inhibition of SAMHD1 dNTPase by tetramer destabilization.

ABSTRACT: 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 ? 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.

SUBMITTER: Seamon KJ 

PROVIDER: S-EPMC4105058 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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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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