Small molecule inhibition of SAMHD1 dNTPase by tetramer destabilization

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

doi:10.1021/ja5035717

Small molecule inhibition of SAMHD1 dNTPase by tetramer destabilization

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

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	https://doi.org/10.1021/ja5035717
State	Published - Jul 16 2014

ASJC Scopus subject areas

Catalysis
Chemistry(all)
Biochemistry
Colloid and Surface Chemistry

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10.1021/ja5035717

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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.",

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AU - Hansen, Erik C.

AU - Kadina, Anastasia P.

AU - Kashemirov, Boris A.

AU - McKenna, Charles E.

AU - Bumpus, Namandjé N.

AU - Stivers, James T.

PY - 2014/7/16

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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.

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Small molecule inhibition of SAMHD1 dNTPase by tetramer destabilization

Abstract

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