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- EMDB-62577: Cryo-EM structure of HsClpP bound to CLPP-2068 -

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Basic information

Entry
Database: EMDB / ID: EMD-62577
TitleCryo-EM structure of HsClpP bound to CLPP-2068
Map data
Sample
  • Complex: Complex of HsClpP with CLPP-2068
    • Protein or peptide: ATP-dependent Clp protease proteolytic subunit, mitochondrial
  • Ligand: 3-[[(7~{R})-2-[(4-bromophenyl)methylamino]-7-methyl-4-oxidanylidene-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]methyl]benzenecarbonitrile
KeywordsClpP / CLPP-2068 / bicyclic imipridone / methyl groups / Diffuse Large B-Cell Lymphoma / Cryo-EM / ANTITUMOR PROTEIN
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.45 Å
AuthorsZhao H / Yuan Q / Yin W
Funding support China, 1 items
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, 2024-
Header (metadata) releaseJul 16, 2025-
Map releaseJul 16, 2025-
UpdateJul 30, 2025-
Current statusJul 30, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_62577.png

Downloads & links

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Map

FileDownload / File: emd_62577.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 256 pix.
= 186.88 Å		0.73 Å/pix.
x 256 pix.
= 186.88 Å		0.73 Å/pix.
x 256 pix.
= 186.88 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.403
Minimum - Maximum-1.1357993 - 1.9706724
Average (Standard dev.)0.0045264503 (±0.08601467)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 186.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_62577_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_62577_half_map_2.map
Projections & Slices
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Sample components

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Entire : Complex of HsClpP with CLPP-2068

EntireName: Complex of HsClpP with CLPP-2068
Components
  • Complex: Complex of HsClpP with CLPP-2068
    • Protein or peptide: ATP-dependent Clp protease proteolytic subunit, mitochondrial
  • Ligand: 3-[[(7~{R})-2-[(4-bromophenyl)methylamino]-7-methyl-4-oxidanylidene-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]methyl]benzenecarbonitrile

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Supramolecule #1: Complex of HsClpP with CLPP-2068

SupramoleculeName: Complex of HsClpP with CLPP-2068 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: ATP-dependent Clp protease proteolytic subunit, mitochondrial

MacromoleculeName: ATP-dependent Clp protease proteolytic subunit, mitochondrial
type: protein_or_peptide / ID: 1 / Number of copies: 14 / Enantiomer: LEVO / EC number: endopeptidase Clp
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.979637 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: IPIVVEQTGR GERAYDIYSR LLRERIVCVM GPIDDSVASL VIAQLLFLQS ESNKKPIHMY INSPGGVVTA GLAIYDTMQY ILNPICTWC VGQAASMGSL LLAAGTPGMR HSLPNSRIMI HQPSGGARGQ ATDIAIQAEE IMKLKKQLYN IYAKHTKQSL Q VIESAMER ...String:
IPIVVEQTGR GERAYDIYSR LLRERIVCVM GPIDDSVASL VIAQLLFLQS ESNKKPIHMY INSPGGVVTA GLAIYDTMQY ILNPICTWC VGQAASMGSL LLAAGTPGMR HSLPNSRIMI HQPSGGARGQ ATDIAIQAEE IMKLKKQLYN IYAKHTKQSL Q VIESAMER DRYMSPMEAQ EFGILDKVLV HPPQDGEDEP TLVQKEPVEA APAAEPVPAS T

UniProtKB: ATP-dependent Clp protease proteolytic subunit, mitochondrial

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Macromolecule #2: 3-[[(7~{R})-2-[(4-bromophenyl)methylamino]-7-methyl-4-oxidanylide...

MacromoleculeName: 3-[[(7~{R})-2-[(4-bromophenyl)methylamino]-7-methyl-4-oxidanylidene-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]methyl]benzenecarbonitrile
type: ligand / ID: 2 / Number of copies: 14 / Formula: A1EG3
Molecular weightTheoretical: 464.358 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.5 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
30.0 mMTris-HClTris
1.0 mMDTTDithiothreitol

Details: 30 mM Tris-HCl (pH 8.0), 150 mM NaCl and 1 mM DTT
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsPhase plate: OTHER
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number real images: 9086 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 18.0 µm / Nominal defocus min: 8.0 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.45 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4.1) / Number images used: 1480526
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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Atomic model buiding 1

Initial modelPDB ID:

7uvm


Chain - Source name: PDB / Chain - Initial model type: experimental model
Details: the initial model consisted of the complete assembly for PDB entry 7UVM
RefinementSpace: REAL / Protocol: AB INITIO MODEL / Overall B value: 71.74
Output model

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

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