Small Molecule Inhibition of SAMHD1 dNTPase by Tetramer Destabilization
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- 作者：Kyle J. Seamon ; Erik C. Hansen ; Anastasia P. Kadina ; Boris A. Kashemirov ; Charles E. McKenna ; Namandj茅 N. Bumpus ; James T. Stivers
- 刊名：Journal of the American Chemical Society
- 出版年：2014
- 出版时间：July 16, 2014
- 年：2014
- 卷：136
- 期：28
- 页码：9822-9825
- 全文大小：239K
- ISSN：1520-5126
文摘
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 伪 phosphate and 5鈥?carbon that potently inhibits SAMHD1. Although pppCH2dU shows apparent competitive inhibition, it acts by a surprising allosteric mechanism that destabilizes active enzyme tetramer.