Small molecule inhibition of SAMHD1 dNTPase by tetramer destabilization

Kyle J. Seamon, Erik C. Hansen, Anastasia P. Kadina, Boris A. Kashemirov, Charles E. McKenna, Namandje N Bumpus, James Stivers

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)9822-9825
Number of pages4
JournalJournal of the American Chemical Society
Volume136
Issue number28
DOIs
StatePublished - Jul 16 2014

Fingerprint

T-cells
Macrophages
Guanosine Triphosphate
HIV-1
Phosphates
Carbon
Enzymes
T-Lymphocytes
Molecules
Infection

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 journalArticle

Seamon, Kyle J. ; Hansen, Erik C. ; Kadina, Anastasia P. ; Kashemirov, Boris A. ; McKenna, Charles E. ; Bumpus, Namandje N ; Stivers, James. / Small molecule inhibition of SAMHD1 dNTPase by tetramer destabilization. In: Journal of the American Chemical Society. 2014 ; Vol. 136, No. 28. pp. 9822-9825.
@article{8ff2b4564dde4c7cb37eb1d70abf07e5,
title = "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 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.",
author = "Seamon, {Kyle J.} and Hansen, {Erik C.} and Kadina, {Anastasia P.} and Kashemirov, {Boris A.} and McKenna, {Charles E.} and Bumpus, {Namandje N} and James Stivers",
year = "2014",
month = "7",
day = "16",
doi = "10.1021/ja5035717",
language = "English (US)",
volume = "136",
pages = "9822--9825",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "28",

}

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 -