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Here, we reveal structural and mechanistic differences between Pol \u03b3 and RT by studying NRTIs that have comparable efficacy on RT but significantly different affinities for Pol \u03b3. We identified critical discriminator residues in Pol \u03b3 that are fully responsible for its differential response to emtricitabine. More importantly, the topological equivalent residue in RT is essential for activity, thus identifying this region as a hot-spot for inhibitor design.<\/jats:p>","DOI":"10.1073\/pnas.1421733112","type":"journal-article","created":{"date-parts":[[2015,6,29]],"date-time":"2015-06-29T22:55:30Z","timestamp":1435618530000},"page":"8596-8601","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":48,"title":["Probing the structural and molecular basis of nucleotide selectivity by human mitochondrial DNA polymerase \u03b3"],"prefix":"10.1073","volume":"112","author":[{"given":"Christal D.","family":"Sohl","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal R.","family":"Szymanski","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555;"},{"name":"Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, TX 77555;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea C.","family":"Mislak","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christie K.","family":"Shumate","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555;"},{"name":"Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, TX 77555;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheida","family":"Amiralaei","sequence":"additional","affiliation":[{"name":"Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond F.","family":"Schinazi","sequence":"additional","affiliation":[{"name":"Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322;"},{"name":"Veterans Affairs Medical Center, Decatur, GA 30033"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen S.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. Whitney","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555;"},{"name":"Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, TX 77555;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2015,6,29]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1097\/00001432-200002000-00002","article-title":"Mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors: A looming obstacle for long-term antiretroviral therapy?","volume":"13","author":"Brinkman K","year":"2000","unstructured":"K Brinkman, TN Kakuda, Mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors: A looming obstacle for long-term antiretroviral therapy? Curr Opin Infect Dis 13, 5\u201311 (2000).","journal-title":"Curr Opin Infect Dis"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1517\/17425255.2010.526602","article-title":"Nucleoside reverse transcriptase inhibitor toxicity and mitochondrial DNA","volume":"6","author":"Koczor CA","year":"2010","unstructured":"CA Koczor, W Lewis, Nucleoside reverse transcriptase inhibitor toxicity and mitochondrial DNA. Expert Opin Drug Metab Toxicol 6, 1493\u20131504 (2010).","journal-title":"Expert Opin Drug Metab Toxicol"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1002\/em.20223","article-title":"A brief overview of mechanisms of mitochondrial toxicity from NRTIs","volume":"48","author":"Kohler JJ","year":"2007","unstructured":"JJ Kohler, W Lewis, A brief overview of mechanisms of mitochondrial toxicity from NRTIs. Environ Mol Mutagen 48, 166\u2013172 (2007).","journal-title":"Environ Mol Mutagen"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1038\/nrd1201","article-title":"Mitochondrial toxicity of NRTI antiviral drugs: An integrated cellular perspective","volume":"2","author":"Lewis W","year":"2003","unstructured":"W Lewis, BJ Day, WC Copeland, Mitochondrial toxicity of NRTI antiviral drugs: An integrated cellular perspective. Nat Rev Drug Discov 2, 812\u2013822 (2003).","journal-title":"Nat Rev Drug Discov"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.mito.2004.05.018","article-title":"Molecular insights into NRTI inhibition and mitochondrial toxicity revealed from a structural model of the human mitochondrial DNA polymerase","volume":"4","author":"Bienstock RJ","year":"2004","unstructured":"RJ Bienstock, WC Copeland, Molecular insights into NRTI inhibition and mitochondrial toxicity revealed from a structural model of the human mitochondrial DNA polymerase. Mitochondrion 4, 203\u2013213 (2004).","journal-title":"Mitochondrion"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1128\/AAC.48.4.1300-1306.2004","article-title":"Relationship between antiviral activity and host toxicity: Comparison of the incorporation efficiencies of 2\u2032,3\u2032-dideoxy-5-fluoro-3\u2032-thiacytidine-triphosphate analogs by human immunodeficiency virus type 1 reverse transcriptase and human mitochondrial DNA polymerase","volume":"48","author":"Feng JY","year":"2004","unstructured":"JY Feng, , Relationship between antiviral activity and host toxicity: Comparison of the incorporation efficiencies of 2\u2032,3\u2032-dideoxy-5-fluoro-3\u2032-thiacytidine-triphosphate analogs by human immunodeficiency virus type 1 reverse transcriptase and human mitochondrial DNA polymerase. Antimicrob Agents Chemother 48, 1300\u20131306 (2004).","journal-title":"Antimicrob Agents Chemother"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"808","DOI":"10.3109\/00365540903186181","article-title":"Long term adverse effects related to nucleoside reverse transcriptase inhibitors: Clinical impact of mitochondrial toxicity","volume":"41","author":"Maagaard A","year":"2009","unstructured":"A Maagaard, D Kvale, Long term adverse effects related to nucleoside reverse transcriptase inhibitors: Clinical impact of mitochondrial toxicity. Scand J Infect Dis 41, 808\u2013817 (2009).","journal-title":"Scand J Infect Dis"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.antiviral.2006.04.017","article-title":"L-nucleoside enantiomers as antivirals drugs: A mini-review","volume":"71","author":"Math\u00e9 C","year":"2006","unstructured":"C Math\u00e9, G Gosselin, L-nucleoside enantiomers as antivirals drugs: A mini-review. 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Beilstein J Org Chem 6, 38 (2010).","journal-title":"Beilstein J Org Chem"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1080\/07391102.2000.10506561","article-title":"15N-enriched 5-fluorocytosine as a probe for examining unusual DNA structures","volume":"17","author":"Sowers LC","year":"2000","unstructured":"LC Sowers, 15N-enriched 5-fluorocytosine as a probe for examining unusual DNA structures. J Biomol Struct Dyn 17, 713\u2013723 (2000).","journal-title":"J Biomol Struct Dyn"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1126\/science.1131943","article-title":"Fluorine in pharmaceuticals: Looking beyond intuition","volume":"317","author":"M\u00fcller K","year":"2007","unstructured":"K M\u00fcller, C Faeh, F Diederich, Fluorine in pharmaceuticals: Looking beyond intuition. 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Nucleic Acids Res 32, 3053\u20133064 (2004).","journal-title":"Nucleic Acids Res"},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"9630","DOI":"10.1021\/bi980549z","article-title":"Loss of polymerase activity due to Tyr to Phe substitution in the YMDD motif of human immunodeficiency virus type-1 reverse transcriptase is compensated by Met to Val substitution within the same motif","volume":"37","author":"Harris D","year":"1998","unstructured":"D Harris, PN Yadav, VN Pandey, Loss of polymerase activity due to Tyr to Phe substitution in the YMDD motif of human immunodeficiency virus type-1 reverse transcriptase is compensated by Met to Val substitution within the same motif. 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J Med Chem 54, 2727\u20132737 (2011).","journal-title":"J Med Chem"},{"key":"e_1_3_4_37_2","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1002\/prot.1137","article-title":"Molecular dynamics of HIV-1 reverse transcriptase indicates increased flexibility upon DNA binding","volume":"45","author":"Madrid M","year":"2001","unstructured":"M Madrid, JA Lukin, JD Madura, J Ding, E Arnold, Molecular dynamics of HIV-1 reverse transcriptase indicates increased flexibility upon DNA binding. 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Cell 139, 312\u2013324 (2009).","journal-title":"Cell"},{"key":"e_1_3_4_40_2","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S1097-2765(01)00153-8","article-title":"Crystal structure and deletion analysis show that the accessory subunit of mammalian DNA polymerase gamma, Pol gamma B, functions as a homodimer","volume":"7","author":"Carrodeguas JA","year":"2001","unstructured":"JA Carrodeguas, K Theis, DF Bogenhagen, C Kisker, Crystal structure and deletion analysis show that the accessory subunit of mammalian DNA polymerase gamma, Pol gamma B, functions as a homodimer. 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