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UID:https://www.otago.ac.nz/news/events/microbiology-seminar-professor-kurt-krause-department-of-biochemistry
URL:https://www.otago.ac.nz/news/events/microbiology-seminar-professor-kurt-krause-department-of-biochemistry
DTSTART;TZID=Pacific/Auckland:20261102T130000
DTEND;TZID=Pacific/Auckland:20261102T140000
SUMMARY:Microbiology seminar: Professor Kurt Krause, Department of Biochemistry
DESCRIPTION:How a dormant, but essential, enzyme in Pseudomonas aeruginosa is activated 20,000-fold by a cell-wall precursor Glutamate racemase is an essential protein in the important pathogenic bacterium, Pseudomonas aeruginosa. Widespread antibiotic resistance in Pseudomonas has put this bacterium on the World Health Organization’s top list for new antibiotic development. Highly effective antibiotics, e.g. penicillins and cephalosporins, are often found to be inhibitors of enzymes involved in cell wall synthesis. In this vein we targeted Pseudomonas glutamate racemase as part of a drug discovery project. However, we found that the enzyme, when purified in vitro, is essentially "dead" in its natural or "unliganded" state. But, when complexed with a cell wall precursor, UDP-N-acetylmuramate-L-Ala, enzyme activity accelerates by four orders of magnitude and substrate affinity improves more than 10-fold. High-resolution structural studies in the presence and absence of this allosteric activator, the first for this enzyme, detail extensive electrostatic remodelling of the enzyme’s surface to accommodate activator binding. These changes propagate through the enzyme into the active site and have provided clear hypotheses concerning enzyme activation. In addition, analysis of the molecular details of activator binding have allowed us to develop a sequence based predictive binding model. These details should enhance drug target development for this enzyme and could accelerate drug discovery research for anti-Pseudomonas treatments. 
LOCATION:Biochemistry Seminar Room G.13 (BIG13), 710 Cumberland Street, Dunedin
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