In silico Analysis of FtsZ Crystal Structures Towards a New Target for Antibiotics
Kennardy D. Kusuma
A , Renate Griffith B , Elizabeth J. Harry A , Amy L. Bottomley A and Alison T. Ung C D
A The ithree Institute, University of Technology Sydney, Sydney, NSW 2007, Australia.
B Department of Pharmacology, School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia.
C School of Mathematical and Physical Sciences, University of Technology Sydney, Sydney, NSW 2007, Australia.
D Corresponding author. Email: alison.ung@uts.edu.au
Australian Journal of Chemistry 72(3) 184-193 https://doi.org/10.1071/CH18347
Submitted: 19 July 2018 Accepted: 26 October 2018 Published: 21 November 2018
Abstract
The bacterial cell division protein FtsZ is conserved in most bacteria and essential for viability. There have been concerted efforts in developing inhibitors that target FtsZ as potential antibiotics. Key to this is an in-depth understanding of FtsZ structure at the molecular level across diverse bacterial species to ensure inhibitors have high affinity for the FtsZ target in a variety of clinically relevant pathogens. In this study, we show that FtsZ structures differ in three ways: (1) the H7 helix curvature; (2) the dimensions of the interdomain cleft; and (3) the opening/closing mechanism of the interdomain cleft, whereas no differences were observed in the dimensions of the nucleotide-binding pocket and T7 loop. Molecular dynamics simulation may suggest that there are two possible mechanisms for the process of opening and closing of the interdomain cleft on FtsZ structures. This discovery highlights significant differences between FtsZ structures at the molecular level and this knowledge is vital in assisting the design of potent FtsZ inhibitors.
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