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 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. 

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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.

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MD simulations with PMbs

References

Botte, M et al. (2021). Insight into Lipopolysaccharide Translocation by Cryo-EM structures of a LptDE Transporter in Complex with Pro-Macrobodies. bioRxiv 2021.03.23.436624; doi: https://doi.org/10.1101/2021.03.23.436624

Bucher, D and Schenck, S. (2021). Pro-Macrobodies for the enhancement of structure research. International PCT Application (No. EP2021/053794).