Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery

Caseinolytic peptidase P (ClpP) normally collaborates with ATPases associated with diverse activities (AAA+) partner proteins, such as ClpX and ClpC, to carry out energy-dependent degradation of proteins within cells. The ClpP enzyme from Mycobacterium tuberculosis is required for survival of this human pathogen, is a validated drug target, and is unusual in consisting of discrete ClpP1 and ClpP2 rings. We solved the crystal structure of ClpP1P2 bound to peptides that mimic binding of protein substrates and small molecules that mimic binding of a AAA+ partner and cause unregulated rogue proteolysis. These studies explain why two different ClpP rings are required for peptidase activity and provide a foundation for the rational development of drugs that target ClpP1P2 and kill M. tuberculosis.