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

Protein Science : a Publication of the Protein Society
Masayo KotakaDavid K Stammers

Abstract

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 in TMP binding is observed, in which the site is partially closed. Analysis of these structures indicates a sequence of events upon TMP binding, with helix alpha3 shifting position initially, followed by movement of alpha2 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 a...Continue Reading

Citations

Oct 10, 2012·Journal of Medicinal Chemistry·Gabriel Martínez-BotellaThomas A Keating
Oct 31, 2008·Proceedings of the National Academy of Sciences of the United States of America·Christophe CaillatPhilippe Meyer
Oct 3, 2006·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Kamel El OmariDavid K Stammers
Jun 5, 2008·Protein Science : a Publication of the Protein Society·Cecilia CarnrotStaffan Eriksson
Feb 22, 2014·Acta Tropica·Pawan Kumar DohareyJitendra Kumar Saxena
Aug 23, 2012·ACS Chemical Biology·Thomas A KeatingGabriel Martínez-Botella
May 11, 2019·The Journal of Antimicrobial Chemotherapy·Joseph M ReedGreg A Somerville
Apr 14, 2018·Acta Crystallographica. Section D, Structural Biology·Santosh Kumar ChaudharyKanagaraj Sekar
Nov 18, 2018·International Journal of Biological Macromolecules·Santosh Kumar ChaudharyKanagaraj Sekar
Dec 7, 2007·Bioorganic & Medicinal Chemistry Letters·Voula MitsakosCraig A Hutton

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