CryoEM Structure of the Antibacterial Target PBP1b at 3.3 Å Resolution
This week we profile a recent publication in Nature Communications from Dr. Nathanael Caveney (pictured, back, second from left), Dr. Sean Workman (back, third from left), and Dr. Claire Atkinson (back row, far left) in the laboratory of Dr. Natalie Strynadka (front, left) at the Department of Biochemistry and Molecular Biology and Centre for Blood Research in the Life Sciences Institute, UBC.
Can you provide a brief overview of your lab’s current research focus?
In the Strynadka lab, our primary focus is to address the growing threat of antibiotic resistance through the structure-based design of inhibitors that either block existing antibiotic resistance mechanisms, or provide novel therapies by targeting proteins and macromolecular assemblies essential to bacterial viability or pathogenesis.
What is the significance of the findings in this publication?
Amongst one of the greatest drugs in history, the antibiotic penicillin targets and disarms a universal essential membrane localized bacterial enzyme, a so called penicillin binding protein (PBP), that plays a central role in production of the bacterial cell wall protective layer. Despite its importance as a drug target and decades of intensive research by the academic and pharmaceutical sectors, many questions as to its mode of action, conformational dynamics and interactions with substrates and partner enzymes in the cell wall biosynthetic machinery have remained unanswered. In our new work, we use a revolutionary new biophysical technique, single particle cryo Electron Microscopy (cryoEM) in the presence of newly developed membrane mimetics (styrene maleic acid polymers of SMALPs) to capture for the first time dynamic snapshots of this important antibiotic target at atomic resolution, in this case PBP1b from Escherichia coli, informing on new critical functional and structural information of the enzyme activity and paving the way for enhanced structure-guided drug discovery efforts.
What are the next steps for this research?
Never before done but now made possible through the method break throughs in this paper, ongoing work is aimed at capturing additional structures of the cell wall PBPs with their complex peptidoglycan substrates and enzyme partners. These partners and the cell wall they produce change depending if the bacterial cell is at rest, growing, dividing or infecting with the complexes further informing antibiotic discovery efforts.