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

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

Access to Document

10.1021/ja5035717

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, Namandjé N.; Stivers, James T.

In: Journal of the American Chemical Society, Vol. 136, No. 28, 16.07.2014, p. 9822-9825.

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

@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, {Namandj{\'e} N.} and Stivers, {James T.}",

year = "2014",

month = jul,

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, Namandjé N.

AU - Stivers, James T.

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 -

Small molecule inhibition of SAMHD1 dNTPase by tetramer destabilization

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this