CryoEM Structure of Lipopolysaccharide Transporter LptDE Opens the Door to Antibiotics Design
Together with the Basel Biozentrum and the Institute of Medical Microbiology in Zurich, leadXpro solved the structure of the bacterial transporter LptDE to provide structural basis for the design of novel antibiotics.
leadXpro is happy to report, in collaboration with the Basel Biozentrum and the Institute of Medical Microbiology in Zurich, the structure of the bacterial transporter LptDE which was solved by cryo-EM at 3.4 Angstrom. The structure is of particular interest for the discovery of novel antibiotics targeting lipopolysaccharide (LPS) transport on the bacteria outer membrane. It is also the first observation of an LPS transporter “beta-sheet” barrel by cryo-EM.
The work has been published in Nature Communications (Botte et al, 2022)
The remarkable gymnastics of β-barrel outer membrane proteins
An exciting feature of the new structure is its experimental confirmation of a theoretically described conformation of the beta barrel (lateral opening). The lateral opening of lipopolysaccharide (LPS) transporter LptD provides clues at how LPS is released into the bacterial outer membrane: Click the movie to see it.
The design of Pro-Macrobodies (PMbs) for improved cryo-EM and X-rays structures
The high-resolution cryo-EM structures were achieved thanks to complexation with computationally designed, nanobody-based chaperones. The technology was called “Pro-Macrobodies”, or PMbs, and designed and patented by leadXpro. PMbs are novel proteins that fuse target-specific nanobodies with a maltose-binding protein via a rigid linker. The design of the rigid linker was optimized using molecular dynamics simulations. The novel tool provides particle enlargement, improves particle classification, and ultimately gives higher resolution structures.
References
Botte, M., Ni, D., Schenck, S. et al. Cryo-EM structures of a LptDE transporter in complex with Pro-macrobodies offer insight into lipopolysaccharide translocation. Nat Commun 13, 1826 (2022). https://doi.org/10.1038/s41467-022-29459-2
Bucher, D and Schenck, S. (2021). Pro-Macrobodies for the enhancement of structure research. International PCT Application (No. EP2021/053794).