Toggle Main Menu Toggle Search

Open Access padlockePrints

Structures of S. aureus thymidylate kinase reveal an atypical active site configuration and an intermediate conformational state upon substrate binding

Lookup NU author(s): Professor Alastair Hawkins


Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


Methicillin-resistant Staphylococcus aureus (MRSA) poses a major threat to human health, particularly through hospital acquired infection. The spread of MRSA means that novel targets are required to develop potential inhibitors to combat infections caused by such drug-resistant bacteria. Thymidylate kinase (TMK) is attractive as an antibacterial target as it is essential for providing components for DNA synthesis. Here, we report crystal structures of unliganded and thymidylate-bound forms of S. aureus thymidylate kinase (SaTMK). His-tagged and untagged SaTMK crystallize with differing lattice packing and show variations in conformational states for unliganded and thymidylate (TMP) bound forms. In addition to open and closed forms of SaTMK, an intermediate conformation inTMP binding is observed, in which the site is partially closed. Analysis of these structures indicates a sequence of events upon TMP binding, with helix α3 shifting position initially, followed by movement of α2 to close the substrate site. In addition, we observe significant conformational differences in the TMP-binding site in SaTMK as compared to available TMK structures from other bacterial species, Escherichia coli and Mycobacterium tuberculosis as well as human TMK. In SaTMK, Arg 48 is situated at the base of the TMP-binding site, close to the thymine ring, whereas a cis-proline occupies the equivalent position in other TMKs. The observed TMK structural differences mean that design of compounds highly specific for the S. aureus enzyme looks possible; such inhibitors could minimize the transfer of drug resistance between different bacterial species. Copyright © 2006 The Protein Society.

Publication metadata

Author(s): Kotaka M, Dhaliwal B, Ren J, Nichols CE, Angell R, Lockyer M, Hawkins AR, Stammers DK

Publication type: Article

Publication status: Published

Journal: Protein Science

Year: 2006

Volume: 15

Issue: 4

Pages: 774-784

ISSN (print): 0961-8368

ISSN (electronic): 1469-896X

Publisher: Wiley-Blackwell


DOI: 10.1110/ps.052002406

PubMed id: 16522804


Altmetrics provided by Altmetric