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- PDB-9kuf: Cryo-EM structure of HsClpP bound to CLPP-2068 -

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Basic information

Entry
Database: PDB / ID: 9kuf
TitleCryo-EM structure of HsClpP bound to CLPP-2068
ComponentsATP-dependent Clp protease proteolytic subunit, mitochondrial
KeywordsANTITUMOR PROTEIN / ClpP / CLPP-2068 / bicyclic imipridone / methyl groups / Diffuse Large B-Cell Lymphoma / Cryo-EM
Function / homology
Function and homology information


membrane protein proteolysis / mitochondrial protein catabolic process / endopeptidase Clp / endopeptidase Clp complex / ATP-dependent peptidase activity / protein quality control for misfolded or incompletely synthesized proteins / Mitochondrial protein degradation / proteolysis involved in protein catabolic process / peptidase activity / ATPase binding ...membrane protein proteolysis / mitochondrial protein catabolic process / endopeptidase Clp / endopeptidase Clp complex / ATP-dependent peptidase activity / protein quality control for misfolded or incompletely synthesized proteins / Mitochondrial protein degradation / proteolysis involved in protein catabolic process / peptidase activity / ATPase binding / endopeptidase activity / mitochondrial matrix / serine-type endopeptidase activity / mitochondrion / proteolysis / identical protein binding
Similarity search - Function
ClpP, Ser active site / Endopeptidase Clp serine active site. / ClpP, histidine active site / Endopeptidase Clp histidine active site. / ATP-dependent Clp protease proteolytic subunit / Clp protease proteolytic subunit /Translocation-enhancing protein TepA / Clp protease / ClpP/crotonase-like domain superfamily
Similarity search - Domain/homology
: / ATP-dependent Clp protease proteolytic subunit, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.45 Å
AuthorsZhao, H. / Yuan, Q. / Yin, W.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: J Med Chem / Year: 2025
Title: Harnessing the Magic Methyl Effect: Discovery of CLPP-2068 as a Novel ClpP Activator for the Treatment of Diffuse Large B-Cell Lymphoma.
Authors: Mingyang Sun / Beijing Chen / Dan Teng / Hongshen Zhao / Yilie Liao / Chun Zhang / Qi Huang / Huicong Ma / Chongyu Wang / Xinyi Lin / Peng Yu / Qingning Yuan / Jinghua Yu / Lei Xu / Xiaobei ...Authors: Mingyang Sun / Beijing Chen / Dan Teng / Hongshen Zhao / Yilie Liao / Chun Zhang / Qi Huang / Huicong Ma / Chongyu Wang / Xinyi Lin / Peng Yu / Qingning Yuan / Jinghua Yu / Lei Xu / Xiaobei Hu / Fei Ye / Xingxing Diao / Mingyue Zheng / Wanchao Yin / Yubo Zhou / Jia Li / Mingliang Wang /
Abstract: The "magic methyl effect" has facilitated the successful development of numerous pharmaceutical compounds. During the development of ClpP activators, we found that incorporating methyl groups into ...The "magic methyl effect" has facilitated the successful development of numerous pharmaceutical compounds. During the development of ClpP activators, we found that incorporating methyl groups into the bicyclic imipridone scaffolds significantly enhanced the activator activity at the enzymatic level. Further structure-activity relationship studies led to the identification of a highly promising compound, , which exhibited an EC value of 50.4 nM. Cryo-electron microscopy techniques and computational analyses demonstrated that the introduction of methyl groups facilitated the formation of additional CH-π interactions between and ClpP, thereby lowering the energy barriers during the binding process. Furthermore, additional pharmaceutical analyses indicated that exhibited favorable pharmacokinetic properties and effectively mitigated the potential hERG toxicity observed in imipridone-based ClpP activators. Collectively, , developed using the magic methylation strategy, holds potential as a therapeutic agent for the treatment of diffuse large B-cell lymphoma, thereby expanding the clinical indications for ClpP activators.
History
DepositionDec 3, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 16, 2025Provider: repository / Type: Initial release
Revision 1.0Jul 16, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 16, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 16, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 16, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 16, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ATP-dependent Clp protease proteolytic subunit, mitochondrial
B: ATP-dependent Clp protease proteolytic subunit, mitochondrial
C: ATP-dependent Clp protease proteolytic subunit, mitochondrial
D: ATP-dependent Clp protease proteolytic subunit, mitochondrial
E: ATP-dependent Clp protease proteolytic subunit, mitochondrial
F: ATP-dependent Clp protease proteolytic subunit, mitochondrial
G: ATP-dependent Clp protease proteolytic subunit, mitochondrial
H: ATP-dependent Clp protease proteolytic subunit, mitochondrial
I: ATP-dependent Clp protease proteolytic subunit, mitochondrial
J: ATP-dependent Clp protease proteolytic subunit, mitochondrial
K: ATP-dependent Clp protease proteolytic subunit, mitochondrial
L: ATP-dependent Clp protease proteolytic subunit, mitochondrial
M: ATP-dependent Clp protease proteolytic subunit, mitochondrial
N: ATP-dependent Clp protease proteolytic subunit, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)342,21628
Polymers335,71514
Non-polymers6,50114
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
ATP-dependent Clp protease proteolytic subunit, mitochondrial / Endopeptidase Clp


Mass: 23979.637 Da / Num. of mol.: 14
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CLPP / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q16740, endopeptidase Clp
#2: Chemical
ChemComp-A1EG3 / 3-[[(7~{R})-2-[(4-bromophenyl)methylamino]-7-methyl-4-oxidanylidene-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]methyl]benzenecarbonitrile


Mass: 464.358 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C23H22BrN5O
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Complex of HsClpP with CLPP-2068 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8 / Details: 30 mM Tris-HCl (pH 7.5), 150 mM NaCl and 1 mM DTT
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
230 mMTrisTris-HCl1
31 mMDithiothreitolDTT1
SpecimenConc.: 1.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 18000 nm / Nominal defocus min: 8000 nm / Alignment procedure: BASIC
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of real images: 9086
EM imaging opticsPhase plate: OTHER

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
7Coot2.5.8model fitting
12cryoSPARC4.4.13D reconstruction
13PHENIX1.21model refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.45 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1480526 / Symmetry type: POINT
Atomic model buildingB value: 71.74 / Protocol: AB INITIO MODEL / Space: REAL
Atomic model buildingPDB-ID: 7UVM

7uvm


Accession code: 7UVM
Details: the initial model consisted of the complete assembly for PDB entry 7UVM
Source name: PDB / Type: experimental model

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