Journal article
Structural Determinants Defining the Allosteric Inhibition of an Essential Antibiotic Target
TP Soares da Costa, S Desbois, C Dogovski, MA Gorman, NE Ketaren, JJ Paxman, T Siddiqui, LM Zammit, BM Abbott, RM Robins-Browne, MW Parker, GB Jameson, NE Hall, S Panjikar, MA Perugini
Structure | CELL PRESS | Published : 2016
Abstract
Dihydrodipicolinate synthase (DHDPS) catalyzes the first committed step in the lysine biosynthesis pathway of bacteria. The pathway can be regulated by feedback inhibition of DHDPS through the allosteric binding of the end product, lysine. The current dogma states that DHDPS from Gram-negative bacteria are inhibited by lysine but orthologs from Gram-positive species are not. The 1.65-Å resolution structure of the Gram-negative Legionella pneumophila DHDPS and the 1.88-Å resolution structure of the Gram-positive Streptococcus pneumoniae DHDPS bound to lysine, together with comprehensive functional analyses, show that this dogma is incorrect. We subsequently employed our crystallographic data ..
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Awarded by Australian Research Council
Funding Acknowledgements
We would firstly like to acknowledge the support and assistance of the friendly staff at the CSIRO Collaborative Crystallisation Center (www.csiro.au/C3), Melbourne, Australia, and the beamline scientists at the Australian Synchrotron, VIC, Australia. We would also like to thank Prof. Elizabeth Hartland (Department of Microbiology and Immunology, The University of Melbourne) for providing genomic DNA from L. pneumophila and A/Prof. Geoffrey Hogg (Microbiological Diagnostic Unit, University of Melbourne, Public Health Laboratory Network, Department of Health and Aging, Australia) for providing genomic DNA from S. pneumoniae. M.A.P. and S.P. acknowledge the Australian Research Council for funding support (DP150103313), and T.P.S.C. and M.W.P. the National Health and Medical Research Council of Australia for fellowship support (APP1091976 and APP1021645). J.J.P. was funded by an Australian Synchrotron fellowship. Funding from the Victorian Government Operational Infrastructure Support Scheme to St Vincent's Institute is acknowledged. We would also like to acknowledge the La Trobe University-Comprehensive Proteomics Platform for providing infrastructure and expertise. Finally, we thank all members of the Perugini laboratory for helpful discussions during the preparation of the manuscript.