9DW3

Human mitochondrial ClpP in complex with Bortezomib

Summary for 9DW3

• Entry DOI: 10.2210/pdb9dw3/pdb
• EMDB information: 47234
• Descriptor: ATP-dependent Clp protease proteolytic subunit, mitochondrial, N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE (2 entities in total)
• Functional Keywords: mitochondrial protein, serine protease, structural protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 14
• Total formula weight: 342678.48

Authors

Chen, W. (deposition date: 2024-10-08, release date: 2025-10-15, Last modification date: 2026-03-11)

Primary citation

Chen, W.,Lander, G.C.,Yang, J.
Cryo-EM structures of human ClpXP reveal mechanisms of assembly and proteolytic activation.
Nat Commun, 17:1064-1064, 2026

PubMed Abstract: The human ClpXP complex (hClpXP) orchestrates mitochondrial protein quality control through targeted degradation of misfolded and unnecessary proteins. While bacterial ClpXP systems are well characterized, the assembly and regulation of human ClpXP remain poorly understood. In this study, we elucidate the complete assembly pathway of hClpXP through high-resolution cryo-electron microscopy (cryo-EM) structures. Our findings confirm that hClpP exists as a single-ring heptamer in isolation and reveal a previously undocumented initial assembly complex in which hexameric hClpX first engages with heptameric hClpP. We further demonstrate how this interaction drives substantial conformational rearrangements that facilitate the formation of tetradecameric hClpP within the fully assembled complex. Notably, we characterize a unique eukaryotic sequence in hClpX, termed the E-loop, which plays a critical role in stabilizing hexamer assembly and maintaining ATPase activity. Additionally, we show that peptide binding at the hClpP active site triggers further structural changes essential for achieving full proteolytic competence. Together, these structures provide unprecedented mechanistic insights into the stepwise assembly and activation of hClpXP, significantly advancing our understanding of this essential mitochondrial protein degradation machinery.

PubMed: 41593052
DOI: 10.1038/s41467-025-67010-1

Experimental method

ELECTRON MICROSCOPY (2.4 Å)