PDBsum entry 1xmr

Transferase

PDB id: 1xmr

Contents

Protein chains

190 a.a.

207 a.a.

Ligands

TTP ×4

Metals

_ZN ×4

_MG ×2

Waters ×144

References listed in PDB file

Key reference

Title

Structures of thymidine kinase 1 of human and mycoplasmic origin.

Authors

M.Welin, U.Kosinska, N.E.Mikkelsen, C.Carnrot, C.Zhu, L.Wang, S.Eriksson, B.Munch-Petersen, H.Eklund.

Ref.

Proc Natl Acad Sci U S A, 2004, 101, 17970-17975. [DOI no: 10.1073/pnas.0406332102]

PubMed id

15611477

Abstract

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.

Figure 1.
Fig. 1. Structures of hTK1 and Uu-TK. (A) Structural alignment of the sequences of TKs from human (P04183 [GenBank] ), Dictyostelium discoideum (AAB03673 [GenBank] 1), Vaccinia virus (AAB96503 [GenBank] 1), B. cereus (ZP_00241105.1), E. coli (NP_287483 [GenBank] .1), and U. urealyticum (U. parvum) (NP_078433 [GenBank] ). Secondary structure elements for hTK1 are shown above the alignment in brown, and those for Uu-TK are shown below in green. The P loop and the two zinc coordinating sequences are boxed. (B) Subunit structure of hTK1 with dTTP colored according to atom type. Mg2+ is shown in yellow, and Zn2+ is shown in gray. (C) Subunit structure of Uu-TK with dTTP, Mg2+, and Zn2+ shown in same colors as in B. hTK1 and Uu-TK are tetramers. (D and E) hTK1 (D) and Uu-TK (E) tetramers shown in different views. The C-terminal helix in Uu-TK interacts with a helix on the adjacent monomer.

Figure 2.
Fig. 2. Lasso domain with structural Zn2+. The coordination of Zn2+ is shown as present in hTK1. In Uu-TK, the coordinating amino acids are C153, C156, C191, and H194. The lasso is shown in orange for hTK1. In Uu-TK, this loop is slightly longer (shown in green). Additionally, the hydrogen bonding from the conserved Arg-Tyr couple is shown.