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

    Research output: Contribution to journalJournal articleResearchpeer-review

    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.
    Original languageEnglish
    JournalProceedings of the National Academy of Science of the United States of America
    Volume101
    Issue number52
    Pages (from-to)17970-17975
    ISSN0027-8424
    DOIs
    Publication statusPublished - 2004

    Keywords

    • crystal structure
    • deoxynucleotide metabolism
    • prodrug activation
    • thymidine kinase 1
    • cytosolic thymidine kinase
    • TK1

    Cite this

    Welin, M., Kosinska, U., Mikkelsen, N-E., Carnrot, C., Zhu, C., Wang, L., ... 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
    Welin, Martin ; Kosinska, Urszula ; Mikkelsen, Nils-Egil ; Carnrot, Cecilia ; Zhu, Chunying ; Wang, Lyia ; Eriksson, Staffan ; Munch-Petersen, Birgitte ; Eklund, Hans. / Structures of thymidine kinase 1 of human and mycoplasma origin. In: Proceedings of the National Academy of Science of the United States of America. 2004 ; Vol. 101, No. 52. pp. 17970-17975.
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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.",
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    author = "Martin Welin and Urszula Kosinska and Nils-Egil Mikkelsen and Cecilia Carnrot and Chunying Zhu and Lyia Wang and Staffan Eriksson and Birgitte Munch-Petersen and Hans Eklund",
    year = "2004",
    doi = "10.1073/pnas.0406332102",
    language = "English",
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    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, vol. 101, no. 52, pp. 17970-17975. https://doi.org/10.1073/pnas.0406332102

    Structures of thymidine kinase 1 of human and mycoplasma origin. / Welin, Martin; Kosinska, Urszula; Mikkelsen, Nils-Egil; Carnrot, Cecilia; Zhu, Chunying; Wang, Lyia; Eriksson, Staffan; Munch-Petersen, Birgitte; Eklund, Hans.

    In: Proceedings of the National Academy of Science of the United States of America, Vol. 101, No. 52, 2004, p. 17970-17975.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Structures of thymidine kinase 1 of human and mycoplasma origin

    AU - Welin, Martin

    AU - Kosinska, Urszula

    AU - Mikkelsen, Nils-Egil

    AU - Carnrot, Cecilia

    AU - Zhu, Chunying

    AU - Wang, Lyia

    AU - Eriksson, Staffan

    AU - Munch-Petersen, Birgitte

    AU - Eklund, Hans

    PY - 2004

    Y1 - 2004

    N2 - 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.

    AB - 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.

    KW - krystal struktur

    KW - deoxynucleotid metabolisme

    KW - prodrug aktivering

    KW - thymidin kinase 1

    KW - cytosol thymidinkinase

    KW - TK1

    KW - crystal structure

    KW - deoxynucleotide metabolism

    KW - prodrug activation

    KW - thymidine kinase 1

    KW - cytosolic thymidine kinase

    KW - TK1

    U2 - 10.1073/pnas.0406332102

    DO - 10.1073/pnas.0406332102

    M3 - Journal article

    VL - 101

    SP - 17970

    EP - 17975

    JO - Proceedings of the National Academy of Sciences of the United States of America

    JF - Proceedings of the National Academy of Sciences of the United States of America

    SN - 0027-8424

    IS - 52

    ER -