ATP-dependent Clp protease ATP-binding subunit ClpC1 (ClpC1)

ATP-dependent Clp protease ATP-binding subunit ClpC1 is an essential AAA+ ATPase in Mycobacterium tuberculosis that acts as a regulatory chaperone for the ClpP1P2 proteolytic complex (UniProt: P9WPB7). It plays a vital role in bacterial protein quality control by identifying, unfolding, and feeding damaged or regulatory proteins into the ClpP protease for degradation (PubMed: 21454742). Because it is indispensable for the survival of the pathogen in both active and dormant states, ClpC1 has emerged as a high-priority target for novel antibiotic development (PubMed: 24439371). Several potent natural products, such as Cyclomarin A, Lassomycin, and Ecumicin, exert their antimicrobial effects by binding to specific domains of ClpC1 (PubMed: 25557061). These interactions typically lead to either the inhibition of the protease's function or the induction of uncontrolled, lethal proteolysis within the bacterial cell (PubMed: 29305401). Targeting ClpC1 is particularly promising for treating multi-drug resistant tuberculosis because its mechanism of action is distinct from existing clinical treatments. Research into ClpC1 inhibitors continues to expand the chemical space for anti-mycobacterial agents while providing insights into the complex regulation of bacterial proteostasis.

Other names

ClpCAAA+ ATPase ClpC1Caseinolytic protease C1Rv3596cMtb ClpC1

Drugs target ClpC1 by binding to its N-terminal domain or D1 domain, which either inhibits the ATPase-dependent unfolding of substrates or dysregulates the ClpP1P2 protease complex, leading to lethal, non-specific protein degradation or loss of essential protein turnover.