Sugar ring alignment and dynamics underline cytarabine and gemcitabine inhibition on Pol η catalyzed DNA synthesis

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dc.citation.articleNumber107361en_US
dc.citation.issueNumber6en_US
dc.citation.journalTitleJournal of Biological Chemistryen_US
dc.citation.volumeNumber300en_US
dc.contributor.authorChang, Caleben_US
dc.contributor.authorZhou, Graceen_US
dc.contributor.authorLee Luo, Christieen_US
dc.contributor.authorEleraky, Sarahen_US
dc.contributor.authorMoradi, Madelineen_US
dc.contributor.authorGao, Yangen_US
dc.date.accessioned2024-10-08T13:27:47Zen_US
dc.date.available2024-10-08T13:27:47Zen_US
dc.date.issued2024en_US
dc.description.abstractNucleoside analogue drugs are pervasively used as antiviral and chemotherapy agents. Cytarabine and gemcitabine are anti-cancer nucleoside analogue drugs that contain C2′ modifications on the sugar ring. Despite carrying all the required functional groups for DNA synthesis, these two compounds inhibit DNA extension once incorporated into DNA. It remains unclear how the C2′ modifications on cytarabine and gemcitabine affect the polymerase active site during substrate binding and DNA extension. Using steady-state kinetics, static and time-resolved X-ray crystallography with DNA polymerase η (Pol η) as a model system, we showed that the sugar ring C2′ chemical groups on cytarabine and gemcitabine snugly fit within the Pol η active site without occluding the steric gate. During DNA extension, Pol η can extend past gemcitabine but with much lower efficiency past cytarabine. The Pol η crystal structures show that the -OH modification in the β direction on cytarabine locks the sugar ring in an unfavorable C2′-endo geometry for product formation. On the other hand, the addition of fluorine atoms on gemcitabine alters the proper conformational transition of the sugar ring for DNA synthesis. Our study illustrates mechanistic insights into chemotherapeutic drug inhibition and resistance and guides future optimization of nucleoside analogue drugs.en_US
dc.identifier.citationChang, C., Zhou, G., Luo, C. L., Eleraky, S., Moradi, M., & Gao, Y. (2024). Sugar ring alignment and dynamics underline cytarabine and gemcitabine inhibition on Pol η catalyzed DNA synthesis. Journal of Biological Chemistry, 300(6). https://doi.org/10.1016/j.jbc.2024.107361en_US
dc.identifier.digitalPIIS0021925824018623en_US
dc.identifier.doihttps://doi.org/10.1016/j.jbc.2024.107361en_US
dc.identifier.urihttps://hdl.handle.net/1911/117913en_US
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.rightsExcept where otherwise noted, this work is licensed under a Creative Commons Attribution (CC BY) license. Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleSugar ring alignment and dynamics underline cytarabine and gemcitabine inhibition on Pol η catalyzed DNA synthesisen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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