The functional oligomeric state of the HsClpXP complex consists of 14 HsClpP subunits forming a cylinder of two heptameric rings (Figure 1Bi) that is capped at each end by six HsClpX subunits forming the hexameric ring typical of AAA+ ATPases. In this configuration, the catalytic residues of HsClpP (Ser153, His178, and Asp227) (Figure 1Bii) are enclosed within the lumen of the ClpP cylinder to prevent unspecific proteolytic activities,while HsClpX serves as thegatekeeper that recognizes only specific proteins and targets them for degradation4 (Figure 1C). The interaction between the HsClpX and HsClpP oligomers is stabilized by the highly dynamic docking interactions of the ATPase’s IGF loops (L439-G440-F441 within the E436−G450 region of HsClpX) with the hydrophobic pockets formed by neighboring HsClpP subunits at the ClpX−ClpP interface.