Small Molecule Inhibition of SAMHD1 dNTPase by Tetramer Destabilization

[Image: see text] 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′ carb...

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Autores principales: Seamon, Kyle J., Hansen, Erik C., Kadina, Anastasia P., Kashemirov, Boris A., McKenna, Charles E., Bumpus, Namandjé N., Stivers, James T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105058/
https://www.ncbi.nlm.nih.gov/pubmed/24983818
http://dx.doi.org/10.1021/ja5035717
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author Seamon, Kyle J.
Hansen, Erik C.
Kadina, Anastasia P.
Kashemirov, Boris A.
McKenna, Charles E.
Bumpus, Namandjé N.
Stivers, James T.
author_facet Seamon, Kyle J.
Hansen, Erik C.
Kadina, Anastasia P.
Kashemirov, Boris A.
McKenna, Charles E.
Bumpus, Namandjé N.
Stivers, James T.
author_sort Seamon, Kyle J.
collection PubMed
description [Image: see text] 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 pppCH(2)dU shows apparent competitive inhibition, it acts by a surprising allosteric mechanism that destabilizes active enzyme tetramer.
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spelling pubmed-41050582015-07-01 Small Molecule Inhibition of SAMHD1 dNTPase by Tetramer Destabilization Seamon, Kyle J. Hansen, Erik C. Kadina, Anastasia P. Kashemirov, Boris A. McKenna, Charles E. Bumpus, Namandjé N. Stivers, James T. J Am Chem Soc [Image: see text] 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 pppCH(2)dU shows apparent competitive inhibition, it acts by a surprising allosteric mechanism that destabilizes active enzyme tetramer. American Chemical Society 2014-07-01 2014-07-16 /pmc/articles/PMC4105058/ /pubmed/24983818 http://dx.doi.org/10.1021/ja5035717 Text en Copyright © 2014 American Chemical Society Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html)
spellingShingle Seamon, Kyle J.
Hansen, Erik C.
Kadina, Anastasia P.
Kashemirov, Boris A.
McKenna, Charles E.
Bumpus, Namandjé N.
Stivers, James T.
Small Molecule Inhibition of SAMHD1 dNTPase by Tetramer Destabilization
title Small Molecule Inhibition of SAMHD1 dNTPase by Tetramer Destabilization
title_full Small Molecule Inhibition of SAMHD1 dNTPase by Tetramer Destabilization
title_fullStr Small Molecule Inhibition of SAMHD1 dNTPase by Tetramer Destabilization
title_full_unstemmed Small Molecule Inhibition of SAMHD1 dNTPase by Tetramer Destabilization
title_short Small Molecule Inhibition of SAMHD1 dNTPase by Tetramer Destabilization
title_sort small molecule inhibition of samhd1 dntpase by tetramer destabilization
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105058/
https://www.ncbi.nlm.nih.gov/pubmed/24983818
http://dx.doi.org/10.1021/ja5035717
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