Structures of thymidine kinase 1 of human and mycoplasmic origin.
Cytosolic thymidine kinase 1, TK1, is a well known cell-cycle-regulated enzyme of importance in nucleotide metabolism as well as an activator of antiviral and anticancer drugs such as 3'-azido-3'-deoxythymidine (AZT). We have now determined the structures of the TK1 family, the human and Ureaplasma urealyticum enzymes, in complex with the feedback inhibitor dTTP. The TK1s have a tetrameric structure in which each subunit contains an alpha/beta-domain that is similar to ATPase domains of members of the RecA structural family and a domain 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 binding 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.
Welin
Martin
M
Department of Molecular Biology, Swedish University of Agricultural Sciences, S-751 24 Uppsala, Sweden.
Kosinska
Urszula
U
Mikkelsen
Nils-Egil
NE
Carnrot
Cecilia
C
Zhu
Chunying
C
Wang
Liya
L
Eriksson
Staffan
S
Munch-Petersen
Birgitte
B
Eklund
Hans
H
D000595:Amino Acid Sequence; D000963:Antimetabolites / Q000494:pharmacology; D001665:Binding Sites; D003460:Crystallization; D003853:Deoxyribonucleosides / Q000737:chemistry; D019143:Evolution, Molecular; D006801:Humans; D006860:Hydrogen Bonding; D007477:Ions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009174:Mycoplasma / Q000201:enzymology*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D013937:Thymidine Kinase / Q000737:chemistry*; D013942:Thymine Nucleotides / Q000737:chemistry; D016990:Ureaplasma urealyticum / Q000201:enzymology; D015215:Zidovudine / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry
D000963:Antimetabolites; D003853:Deoxyribonucleosides; D007477:Ions; D013942:Thymine Nucleotides; D015215:Zidovudine; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D015032:Zinc; C024157:thymidine 5'-triphosphate