Clofarabine Targets the Large Subunit (α) of Human Ribonucleotide Reductase in Live Cells by Assembly into Persistent Hexamers
Available in PMC 2013 July 27
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Springer Science + Business Media B.V.
2013
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| Online Access: | http://hdl.handle.net/1721.1/82029 https://orcid.org/0000-0001-5486-2755 https://orcid.org/0000-0001-8076-4489 |
| _version_ | 1826217436447244288 |
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| author | Aye, Yimon Long, Marcus J.C. Chittuluru, Johnathan Asturias, Francisco J. Stubbe, JoAnne Brignole, Edward J Drennan, Catherine L |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Aye, Yimon Long, Marcus J.C. Chittuluru, Johnathan Asturias, Francisco J. Stubbe, JoAnne Brignole, Edward J Drennan, Catherine L |
| author_sort | Aye, Yimon |
| collection | MIT |
| description | Available in PMC 2013 July 27 |
| first_indexed | 2024-09-23T17:03:37Z |
| format | Article |
| id | mit-1721.1/82029 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T17:03:37Z |
| publishDate | 2013 |
| publisher | Springer Science + Business Media B.V. |
| record_format | dspace |
| spelling | mit-1721.1/820292022-09-29T23:22:37Z Clofarabine Targets the Large Subunit (α) of Human Ribonucleotide Reductase in Live Cells by Assembly into Persistent Hexamers Aye, Yimon Long, Marcus J.C. Chittuluru, Johnathan Asturias, Francisco J. Stubbe, JoAnne Brignole, Edward J Drennan, Catherine L Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemistry Aye, Yimon Brignole, Edward J. Drennan, Catherine L. Stubbe, JoAnne Available in PMC 2013 July 27 Clofarabine (ClF) is a drug used in the treatment of leukemia. One of its primary targets is human ribonucleotide reductase (hRNR), a dual-subunit, (α2)m(β2)n, regulatory enzyme indispensable in de novo dNTP synthesis. We report that, in live mammalian cells, ClF targets hRNR by converting its α-subunit into kinetically stable hexamers. We established mammalian expression platforms that enabled isolation of functional α and characterization of its altered oligomeric associations in response to ClF treatment. Size exclusion chromatography and electron microscopy documented persistence of in-cell-assembled-α6. Our data validate hRNR as an important target of ClF, provide evidence that in vivo α's quaternary structure can be perturbed by a nonnatural ligand, and suggest small-molecule-promoted, persistent hexamerization as a strategy to modulate hRNR activity. These studies lay foundations for documentation of RNR oligomeric state within a cell. Howard Hughes Medical Institute (Investigator) National Institutes of Health (U.S.) (NIH grant GM29595) National Institutes of Health (U.S.) (NIH grant GM67167) Damon Runyon Cancer Research Foundation (postdoctoral fellowship (DRG2015-09)) Howard Hughes Medical Institute (International Student Fellowship) 2013-11-07T20:41:06Z 2013-11-07T20:41:06Z 2012-07 Article http://purl.org/eprint/type/JournalArticle 10745521 http://hdl.handle.net/1721.1/82029 Aye, Yimon, Edward J. Brignole, Marcus J.C. Long, Johnathan Chittuluru, Catherine L. Drennan, Francisco J. Asturias, and JoAnne Stubbe. “Clofarabine Targets the Large Subunit (α) of Human Ribonucleotide Reductase in Live Cells by Assembly into Persistent Hexamers.” Chemistry & Biology 19, no. 7 (July 2012): 799-805. https://orcid.org/0000-0001-5486-2755 https://orcid.org/0000-0001-8076-4489 en_US http://dx.doi.org/10.1016/j.chembiol.2012.05.015 Chemistry & Biology Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Springer Science + Business Media B.V. PMC |
| spellingShingle | Aye, Yimon Long, Marcus J.C. Chittuluru, Johnathan Asturias, Francisco J. Stubbe, JoAnne Brignole, Edward J Drennan, Catherine L Clofarabine Targets the Large Subunit (α) of Human Ribonucleotide Reductase in Live Cells by Assembly into Persistent Hexamers |
| title | Clofarabine Targets the Large Subunit (α) of Human Ribonucleotide Reductase in Live Cells by Assembly into Persistent Hexamers |
| title_full | Clofarabine Targets the Large Subunit (α) of Human Ribonucleotide Reductase in Live Cells by Assembly into Persistent Hexamers |
| title_fullStr | Clofarabine Targets the Large Subunit (α) of Human Ribonucleotide Reductase in Live Cells by Assembly into Persistent Hexamers |
| title_full_unstemmed | Clofarabine Targets the Large Subunit (α) of Human Ribonucleotide Reductase in Live Cells by Assembly into Persistent Hexamers |
| title_short | Clofarabine Targets the Large Subunit (α) of Human Ribonucleotide Reductase in Live Cells by Assembly into Persistent Hexamers |
| title_sort | clofarabine targets the large subunit α of human ribonucleotide reductase in live cells by assembly into persistent hexamers |
| url | http://hdl.handle.net/1721.1/82029 https://orcid.org/0000-0001-5486-2755 https://orcid.org/0000-0001-8076-4489 |
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