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9DKV

Human mitochondrial ClpP in Apo state

Summary for 9DKV
Entry DOI10.2210/pdb9dkv/pdb
EMDB information46970
DescriptorATP-dependent Clp protease proteolytic subunit, mitochondrial (2 entities in total)
Functional Keywordsprotease, proteolysis, hydrolase
Biological sourceHomo sapiens (human)
Total number of polymer chains14
Total formula weight338518.25
Authors
Uday, A.B.,Zeytuni, N.,Goncalves, M.,Vahidi, S. (deposition date: 2024-09-10, release date: 2025-04-23, Last modification date: 2025-04-30)
Primary citationGoncalves, M.M.,Uday, A.B.,Forrester, T.J.B.,Currie, S.Q.W.,Kim, A.S.,Feng, Y.,Jitkova, Y.,Velyvis, A.,Harkness, R.W.,Kimber, M.S.,Schimmer, A.D.,Zeytuni, N.,Vahidi, S.
Mechanism of allosteric activation in human mitochondrial ClpP protease.
Proc.Natl.Acad.Sci.USA, 122:e2419881122-e2419881122, 2025
Cited by
PubMed Abstract: Human ClpP protease contributes to mitochondrial protein quality control by degrading misfolded proteins. ClpP is overexpressed in cancers such as acute myeloid leukemia (AML), where its inhibition leads to the accumulation of damaged respiratory chain subunits and cell death. Conversely, hyperactivating ClpP with small-molecule activators, such as the recently discovered ONC201, disrupts mitochondrial protein degradation and impairs respiration in cancer cells. Despite its critical role in human health, the mechanism underlying the structural and functional properties of human ClpP remains elusive. Notably, human ClpP is paradoxically activated by active-site inhibitors. All available structures of human ClpP published to date are in the inactive compact or compressed states, surprisingly even when ClpP is bound to an activator molecule such as ONC201. Here, we present structures of human mitochondrial ClpP in the active extended state, including a pair of structures where ClpP is bound to an active-site inhibitor. We demonstrate that amino acid substitutions in the handle region (A192E and E196R) recreate a conserved salt bridge found in bacterial ClpP, stabilizing the extended active state and significantly enhancing ClpP activity. We elucidate the ClpP activation mechanism, highlighting a hormetic effect where substoichiometric inhibitor binding triggers an allosteric transition that drives ClpP into its active extended state. Our findings link the conformational dynamics of ClpP to its catalytic function and provide high-resolution structures for the rational design of potent and specific ClpP inhibitors, with implications for targeting AML and other disorders with ClpP involvement.
PubMed: 40232800
DOI: 10.1073/pnas.2419881122
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (2.81 Å)
Structure validation

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