Cryo-EM Structure of Lipopolysaccharide Transporter LptDE Opens the Door to Antibiotics Design

Bacteria display very different biochemistry from human cells, which can be exploited for designing new antibiotics with less side-effects. Detailed insights into the architecture and function of LptDE transporter complexes has been made possible by new Cryo-EM structures.
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The bacterial lipopolysaccharide (LPS) transporter LptDE is not conserved in humans, but plays a pivotal role in many bacteria assisting the essential transport of lipids to the bacterial outer membrane wall. Previous structures of LptDE were all solved by X-ray crystallography.

We report in Nature Communications, 13, 1826 (2022), the first structure done by cryo electron microscopy (Cryo-EM) and the first structure of LptDE from N. gonorrhoeae. Furthermore, it is also the first observation of an LPS transporter “beta-sheet” barrel by Cryo-EM. 

(a) Structure of LptDE solved by Cryo-EM (b).
Figure 1. (a) Structure of LptDE, solved by Cryo-EM (b), at 3.4 Å resolution.

The remarkable gymnastics of β-barrel outer membrane proteins

Another exciting feature of the new structure is its experimental confirmation of a theoretically described conformation of the beta barrel (lateral opening), which provides clues at how LPS is released into the bacterial outer membrane (Fig. 2). From this structure, it can be envisioned that the transition to the open conformation allows LPS to be released to the outer membrane.

Superimposed structures of partly (cyan) and fully open conformations (red).
Figure 2. Superimposed structures of partly (cyan) and fully open conformations (red).

 

The design of Pro-Macrobodies (PMbs) for improved cryo-EM and X-rays structures

To reach this high-resolution for Cryo-EM structures, LptDE was stabilized through complexation with computationally designed nanobody-based chaperones (Fig. 1). The technology was developed for this work and called “Pro-Macrobodies”, or PMbs. These chaperones are novel proteins that fuse target-specific nanobodies with a maltose-binding protein via a rigid linker (see our news article here). The linker was designed as two proline residues, giving Pro-Macrobodies their name, and predicted to be rigid via molecular dynamics simulations. The novel tool provides particle enlargement, improves particle alignment and classification, reduces preferred orientation of particles upon grid freezing and ultimately gives higher resolution structures.

The structures of the bacterial transporter LptDE will provide structural basis for the design of novel antibiotics.

 

References

Botte, M et al. Insight into Lipopolysaccharide Translocation by Cryo-EM structures of a LptDE Transporter in Complex with Pro-Macrobodies. Nature Communications, 13, 1826 (2022).

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

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