McMaster researchers reveal mechanisms of a molecular motor which could provide novel therapeutic drug targets
Hamilton, ON (May 5, 2017) – Researchers at McMaster University and the Hospital for Sick Children (University of Toronto), have discovered the structure and mechanism of action behind an essential protein required for virulence by Pseudomonas aeruginosa, one of the world’s most drug-resistant pathogens. The findings could be used to design ways to make Pseudomonas aeruginosa less pathogenic.
Type IV pili (T4P) are long helical filaments that extend from the surface of a cell and are used by various bacteria for attachment, movement across solid surfaces, and for the formation of biofilms which encase the bacteria and render antibiotics less effective.
The research published today in Nature Communications (https://www.nature.com/articles/ncomms15091), sheds light on how T4P are assembled and disassembled by the motor proteins of the system, and provides targets for future drug development, as pili are an important virulence factor.
The process of extending a pili from the cell involves a molecular motor protein, PilB, which converts the chemical energy into mechanical energy. Up until now, it was unclear how such movements by PilB could lead to pilus assembly.
The structure of PilB was determined in two states which represents the “before” and “after” states of ATP hydrolysis. PilB was modeled as a ring showing the movements of this protein during the hydrolysis cycle.
“We saw that the pore in the centre of the PilB ring rotated in a clockwise direction, while scooping upwards then relaxing back,” said Lori Burrows, co-author of the study and a scientist of the Michael G. DeGroote Institute for Infectious Disease Research at McMaster University.
It was also found that pore inside the PilT ring, which is responsible for pilus retraction, rotated in a counter clockwise direction and moved downward, pulling pilin subunits out of the pilus fibre.
“These results explain how these key motor proteins power pilus extension and retraction and can be used to design ways to inhibit their activity and render the bacteria less pathogenic to their hosts,” said Burrows.
“These systems are important for virulence in many other pathogens, including those that cause cholera, gonorrhoea, food-borne diseases, and multi drug-resistant hospital acquired infections,” she added. “PilB is highly conserved and inhibitors have the potential to apply to a broad spectrum of bacteria.”
Burrows and Howell have been working together since 2003, and are the co-principle investigators on the grant funded by the Canadian Institutes for Health Research (CIHR).