T3S Injectisome Needle Complex Structures in Four Distinct States Reveal the Basis of Membrane Coupling and Assembly
This week we profile a recent publication in Nature Microbiology from Jinhong Hu (pictured, front right) and Liam Worrall
(back row, third from right) in the laboratory of Dr. Natalie Strynadka (front, left) at the Centre for Blood Research.
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?
The bacterial injectisome, or type III secretion system, is a syringe-shaped macromolecular nanomachine utilized by many pathogenic Gram-negative bacteria including the causative agents of plague, typhoid fever, whooping cough, sexually transmitted infections and major nosocomial infections. The essential role in bacterial infection make it an attractive target for the development of novel antibiotics and vaccines. Understanding the molecular structure of this multi-component, dual-membrane spanning complex is a key step in this process. The technique of cryoelectron microscopy has recently undergone a “resolution revolution”, recognized by the award of the 2017 Nobel Prize in Chemistry, and is now capable of obtaining detailed molecular structures to near atomic resolution. Using cryo-EM, we have captured the injectisome core in multiple distinct assembly stages. This novel structural information allows us to understand how this complex assembles and functions, and paves the way for structure-based design of novel therapeutics.
What are the next steps for this research?
The injectisome mediates infection by directly “injecting” proteins (effectors) into the host to subvert normal cellular function. Our next aim is to try and capture the structure of the injectisome in action, directly visualizing the passage of effectors from the bacterial cytoplasm, through the injectisome, and into the host cell.