Structures of thymidine kinase 1 of human and mycoplasma origin

Martin Welin, Urszula Kosinska, Nils-Egil Mikkelsen, Cecilia Carnrot, Chunying Zhu, Lyia Wang, Staffan Eriksson, Birgitte Munch-Petersen, Hans Eklund

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    Abstract

    Cytosolic thymidine kinase, TK1, is a well-known cell cycle regulated enzyme of importance in nucleotide metabolism as well as an activator of antiviral and anticancer drugs as AZT. We have now determined the first structures of the TK1 family, the human and Ureaplasma urealyticum enzymes, in complex with the feedback inhibitor dTTP. The TK1s have a tetrameric structure where each subunit contains an alfa/beta-domain that is similar to ATPase domains of members of the RecA structural family and a domain of a new type containing a structural zinc. The zinc ion connects beta-structures at the root of a beta-ribbon that forms a stem that widens to a lasso type loop. The thymidine of dTTP is hydrogen bonded to main-chain atoms predominantly coming from the lasso loop. This is in contrast to other deoxyribonucleoside kinases where specific interactions occur with side chains. The TK1 structure differs fundamentally from the structures of the other deoxyribonucleoside kinases indicating a different evolutionary origin.
    OriginalsprogEngelsk
    TidsskriftProceedings of the National Academy of Science of the United States of America
    Vol/bind101
    Udgave nummer52
    Sider (fra-til)17970-17975
    ISSN0027-8424
    DOI
    StatusUdgivet - 2004

    Emneord

    • krystal struktur
    • deoxynucleotid metabolisme
    • prodrug aktivering
    • thymidin kinase 1
    • cytosol thymidinkinase
    • TK1

    Citer dette

    Welin, M., Kosinska, U., Mikkelsen, N-E., Carnrot, C., Zhu, C., Wang, L., Eriksson, S., Munch-Petersen, B., & Eklund, H. (2004). Structures of thymidine kinase 1 of human and mycoplasma origin. Proceedings of the National Academy of Science of the United States of America, 101(52), 17970-17975. https://doi.org/10.1073/pnas.0406332102