Tuberculosis, caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb), infects millions and causes millions of deaths each year. It is a chronic infectious disease of global concern, including in China. The discovery of new targets for tuberculosis treatment and the study of their functional mechanisms are crucial for the development of anti-tuberculosis drugs.
In the strategy for selecting anti-tuberculosis targets, drugs targeting the cell wall pathway are simultaneously used to treat both drug-sensitive and drug-resistant tuberculosis, which is internationally recognized as the most effective strategy against tuberculosis. Therefore, key enzymes in the cell wall pathway are also a hot research topic internationally.
Rv3806c, as a membrane protein phosphoribosyltransferase (PRTase) involved in the production of cell wall precursors, is considered a highly promising new target for anti-tuberculosis drugs. The study of its functional mechanism is expected to provide new insights into the increasingly serious problem of drug-resistant tuberculosis.
On the occasion of World Tuberculosis Day, Academician of the Chinese Academy of Sciences and Professor at Nankai University, Zihou Rao, and the team, along with Assistant Professor Lu Zhang's team from ShanghaiTech University, have revealed the three-dimensional structure of Rv3806c for the first time using cryo-electron microscopy.
The research has elucidated the precise three-dimensional structures of the complex formed by Rv3806c with its receptor substrate and donor substrate, revealing the molecular mechanism by which this protein catalyzes phosphoribosyl transfer on the bacterial cytoplasmic membrane. This provides an important theoretical basis for the development of targeted drugs targeting Rv3806c as a new target. The relevant research results have recently been published in the authoritative journal in the field of microbiology, Nature Microbiology.
The function and overall structure of Rv3806c, as provided by Nankai University. [Image supplied by Nankai University]
The detailed complex structure and function of Rv3806c provided by Nankai University.
This work further elucidates the mechanism of ethambutol resistance caused by mutations in Rv3806c in clinical settings through structural and functional studies. It demonstrates that the phospholipid-binding site located at the trimer interface affects the PRTase of the trimer through a possible allosteric regulation mechanism, thereby mediating clinical ethambutol resistance.
"This work is another important achievement of our collaborative team from three universities focusing on novel targets for anti-tuberculosis cell wall synthesis. It provides a structural basis for the systematic understanding of the molecular mechanisms of Mycobacterium tuberculosis' unique and complex cell wall assembly and the discovery of new anti-tuberculosis drugs targeting the cell wall," said Zhang Lu.
Related paper link: https://doi.org/10.1038/s41564-024-01643-8
