3.3-Å resolution cryo-EM structure of human ribonucleotide reductase with substrate and allosteric regulators bound
Ribonucleotide reductases (RNRs) convert ribonucleotides into deoxyribonucleotides, a reaction essential for DNA replication and repair. Human RNR requires two subunits for activity, the α subunit contains the active site, and the β subunit houses the radical cofactor. Here, we present a 3.3-Å resol...
| Main Authors: | , , , , , , , , |
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| 其他作者: | |
| 格式: | 文件 |
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eLife Sciences Publications, Ltd
2018
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| 在线阅读: | http://hdl.handle.net/1721.1/114937 https://orcid.org/0000-0002-4285-6128 https://orcid.org/0000-0001-8076-4489 https://orcid.org/0000-0001-5486-2755 |
| 总结: | Ribonucleotide reductases (RNRs) convert ribonucleotides into deoxyribonucleotides, a reaction essential for DNA replication and repair. Human RNR requires two subunits for activity, the α subunit contains the active site, and the β subunit houses the radical cofactor. Here, we present a 3.3-Å resolution structure by cryo-electron microscopy (EM) of a dATP-inhibited state of human RNR. This structure, which was determined in the presence of substrate CDP and allosteric regulators ATP and dATP, has three α 2 units arranged in an α 6 ring. At near-atomic resolution, these data provide insight into the molecular basis for CDP recognition by allosteric specificity effectors dATP/ATP. Additionally, we present lower-resolution EM structures of human α 6 in the presence of both the anticancer drug clofarabine triphosphate and β 2 . Together, these structures support a model for RNR inhibition in which β 2 is excluded from binding in a radical transfer competent position when α exists as a stable hexamer. |
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