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 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 9822-9825 |
| Number of pages | 4 |
| Journal | Journal of the American Chemical Society |
| Volume | 136 |
| Issue number | 28 |
| DOIs | |
| State | Published - Jul 16 2014 |
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ASJC Scopus subject areas
- Chemistry(all)
- Catalysis
- Biochemistry
- Colloid and Surface Chemistry
Cite this
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, Namandje N; Stivers, James.
In: Journal of the American Chemical Society, Vol. 136, No. 28, 16.07.2014, p. 9822-9825.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Small molecule inhibition of SAMHD1 dNTPase by tetramer destabilization
AU - Seamon, Kyle J.
AU - Hansen, Erik C.
AU - Kadina, Anastasia P.
AU - Kashemirov, Boris A.
AU - McKenna, Charles E.
AU - Bumpus, Namandje N
AU - Stivers, James
PY - 2014/7/16
Y1 - 2014/7/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84904438593&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904438593&partnerID=8YFLogxK
U2 - 10.1021/ja5035717
DO - 10.1021/ja5035717
M3 - Article
C2 - 24983818
AN - SCOPUS:84904438593
VL - 136
SP - 9822
EP - 9825
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 28
ER -