{"88881":{"#nid":"88881","#data":{"type":"event","title":"(11-1116) Dr. Yimon Aye, Massachusetts Institute of Technology","body":[{"value":"\u003Cp\u003EDr. Yimon Aye, Massachusetts Institute of Technology\n\u003C\/p\u003E\n\u003Cp\u003ETapping into Regulation of Human Ribonucleotide Reductase: Inhibitor-Promoted Assembly of Persistent Hexamers \u0026amp; Insights into Metallocofactor Integrity\n\u003C\/p\u003E\n\u003Cp\u003ERibonucleotide reductase (RNR), a linchpin enzyme in DNA synthesis, is a proven target of cancer drugs. Two distinct subunits, \u00ce\u00b1 and \u00ce\u00b2, complete the active unit required for the catalysis of NDP (N=A,C,G,U) reduction to dNDPs. \u00ce\u00b2 harbors a diferric-tyrosyl radical cofactor that initiates intersubunit electron transfer between itself and \u00ce\u00b1, the NDP reduction site. My studies aim to unravel inhibition mechanisms of Clolar\u00c2\u00ae (ClF) and Triapine\u00c2\u00ae (3AP) that respectively target \u00ce\u00b1 and \u00ce\u00b2. Allosteric regulation on \u00ce\u00b1 directly governs dNTP pools homeostasis and in vitro this leads to specific changes in quaternary structure; yet, whether such oligomeric equilibria are relevant in vivo has remained unanswered. Studies with ClF show (i) both di- and triphosphates (ClFDP and \u00e2\u0080\u0022TP) are reversible hRNR inhibitors; (ii) ClFDP, which was not considered to be an active form of the drug, is a slow-release inhibitor; and (iii) \u00ce\u00b1-targeted inhibition occurs via assembly into hexameric states that remarkably persist beyond inhibitor departure. We progressed to demonstrate that persistent hexamerization is a hallmark of hRNR down-regulation in vivo; thus, ClF induces in-cell assembly of kinetically stable \u00ce\u00b1 hexamers. Our data unveil a new avenue to target a key regulatory enzyme, identify a tractable platform to readout hRNR down-regulation, and shed light on the mechanisms of small-molecule-induced enzyme inactivation by persistent oligomerization. My parallel studies with 3AP suggest that \u00ce\u00b2 inhibition principally arises from radical quenching as opposed to ironchelation. We are progressing to examine these in vitro observations in whole cells to garner insights into 3AP inhibition in vivo.\n\u003C\/p\u003E\n\u003Cp\u003EFor more information contact \u003Ca href=\u0022mailto:wendy.kelly@chemistry.gatech.edu\u0022\u003EProf. Wendy Kelly\u003C\/a\u003E (404-385-1154).\u003C\/p\u003E","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"Dr. Yimon Aye, Massachusetts Institute of Technology\n\nTapping into Regulation of Human Ribonucleotide Reductase: Inhibitor-Promoted Assembly of Persistent Hexamers \u0026amp; Insights into Metallocofactor Integrity","format":"limited_html"}],"field_summary_sentence":[{"value":"Dr. Yimon Aye, Massachusetts Institute of Technology"}],"uid":"27275","created_gmt":"2011-10-10 00:00:00","changed_gmt":"2016-10-08 01:50:53","author":"Shirley Tomes","boilerplate_text":"","field_publication":"","field_article_url":"","field_event_time":{"event_time_start":"2011-11-16T15:00:00-05:00","event_time_end":"2011-11-16T16:00:00-05:00","event_time_end_last":"2011-11-16T16:00:00-05:00","gmt_time_start":"2011-11-16 20:00:00","gmt_time_end":"2011-11-16 21:00:00","gmt_time_end_last":"2011-11-16 21:00:00","rrule":null,"timezone":"America\/New_York"},"extras":[],"groups":[{"id":"85951","name":"School of Chemistry and Biochemistry"}],"categories":[],"keywords":[{"id":"5819","name":"analytical chemistry"}],"core_research_areas":[],"news_room_topics":[],"event_categories":[{"id":"1795","name":"Seminar\/Lecture\/Colloquium"}],"invited_audience":[],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[{"value":"\u003Cstrong\u003EShirley Tomes\u003C\/strong\u003E\u003Cbr \/\u003EChemistry \u0026amp; Biochemistry\u003Cbr \/\u003E\u003Ca href=\u0022http:\/\/www.gatech.edu\/contact\/index.html?id=st81\u0022\u003EContact Shirley Tomes\u003C\/a\u003E\u003Cbr \/\u003E\u003Cstrong\u003E404-894-0591\u003C\/strong\u003E","format":"limited_html"}],"email":[],"slides":[],"orientation":[],"userdata":""}}}