Insights into the Structure and Function of ClpP from the Mycobacterium Genus

Tuberculosis (TB) remains a major global health concern, affecting morbidity and mortality rates significantly across the globe. Major obstacles to global TB control efforts are posed by the emergence of drug-resistant TB, including multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). Therefore, new antibiotics against novel target(s) are urgently needed. Caseinolytic peptidase P (ClpP) represents a novel prospective target for hunting antibiotics against TB. ClpP is a serine protease that aids in the quality control of proteins in the bacterial cell. It has been reported that changes in the ClpP complex have an impact on the virulence and survival of different bacterial pathogens. Understanding the structure of the mycobacterial ClpP can facilitate the design of novel antibiotics against it. The hetero-tetradecameric form of ClpP represents the active form. N-blocked dipeptides (ligands) are necessary for the activation of the ClpP complex leading to proteolysis of misfolded proteins. The sequence comparison of Mtb and Msm ClpP revealed few residues in Mtb ClpP that were different from Msm ClpP. These residues possess different properties, and their interaction with the catalytic triads and the activator might play an important role in the pathogenicity of Mtb. Through comparison of apo- and ligand-bound ClpP structures, we observed that upon the ligand binding, the complex opens up its pores to perform its proteolytic function. A major shift of handle domain was observed which indicated that there might be a major shift in handle domain during the transit from inactive to active form. In addition, this shift of handle domain might play a very important role in the proteolysis as such shift causes the widening of the pore to carry out the protein degradation process. The insights gained in the present study may be useful in the structure-based drug design of novel anti-TB agents.