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- PDB-8ylb: Cocrystal structures of agonists compound 1 with HsClpP -

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Basic information

Entry
Database: PDB / ID: 8ylb
TitleCocrystal structures of agonists compound 1 with HsClpP
ComponentsATP-dependent Clp protease proteolytic subunit, mitochondrial
KeywordsHYDROLASE / Homo sapiens Casein lysing protease P (HsClpP) acute myeloid leukemia (AML) agonists
Function / homology
Function and homology information


membrane protein proteolysis / endopeptidase Clp complex / endopeptidase Clp / ATP-dependent peptidase activity / protein quality control for misfolded or incompletely synthesized proteins / proteolysis involved in protein catabolic process / peptidase activity / ATPase binding / endopeptidase activity / mitochondrial matrix ...membrane protein proteolysis / endopeptidase Clp complex / endopeptidase Clp / ATP-dependent peptidase activity / protein quality control for misfolded or incompletely synthesized proteins / 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)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsZhao, N. / Zhu, Y. / Bao, R.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Rational Design of a Novel Class of Human ClpP Agonists through a Ring-Opening Strategy with Enhanced Antileukemia Activity.
Authors: Xiang, X. / Dai, Z. / Luo, B. / Zhao, N. / Liu, S. / Sui, J. / Huang, J. / Zhou, Y. / Gu, J. / Zhang, J. / Yang, T. / Bao, R. / Luo, Y.
History
DepositionMar 6, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 15, 2024Provider: 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)342,71028
Polymers337,29914
Non-polymers5,41114
Water6,071337
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area48910 Å2
ΔGint-225 kcal/mol
Surface area81000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)120.239, 96.742, 124.542
Angle α, β, γ (deg.)90.00, 94.44, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 24092.797 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) / Strain (production host): BL21(DE3) / References: UniProt: Q16740, endopeptidase Clp
#2: Chemical
ChemComp-A1LZA / 5-[(2-methylphenyl)methyl]-11-(phenylmethyl)-2,5,7,11-tetrazatricyclo[7.4.0.0^{2,6}]trideca-1(9),6-dien-8-one


Mass: 386.489 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: C24H26N4O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 337 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.14 Å3/Da / Density % sol: 42.59 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 1.6 M Li2SO4 and 0.1 M Tris, pH 8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97852 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 10, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97852 Å / Relative weight: 1
ReflectionResolution: 2.15→19.88 Å / Num. obs: 153963 / % possible obs: 99.5 % / Redundancy: 6.9 % / CC1/2: 0.964 / Rmerge(I) obs: 0.248 / Rpim(I) all: 0.103 / Rrim(I) all: 0.269 / Χ2: 1.06 / Net I/σ(I): 5 / Num. measured all: 1061470
Reflection shellResolution: 2.15→2.19 Å / % possible obs: 99.5 % / Redundancy: 7.1 % / Rmerge(I) obs: 0.823 / Num. measured all: 54255 / Num. unique obs: 7595 / CC1/2: 0.871 / Rpim(I) all: 0.328 / Rrim(I) all: 0.886 / Χ2: 1.13 / Net I/σ(I) obs: 2

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Processing

Software
NameVersionClassification
PHENIX(1.19.2_4158: ???)refinement
Aimlessdata scaling
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.15→19.88 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2599 2016 1.31 %
Rwork0.207 --
obs0.2076 153896 99.62 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.15→19.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms18643 0 406 337 19386
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00820001
X-RAY DIFFRACTIONf_angle_d0.94727104
X-RAY DIFFRACTIONf_dihedral_angle_d9.8192704
X-RAY DIFFRACTIONf_chiral_restr0.0553084
X-RAY DIFFRACTIONf_plane_restr0.0083370
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.15-2.20.35161430.28910688X-RAY DIFFRACTION99
2.2-2.260.32671620.268410759X-RAY DIFFRACTION99
2.26-2.330.30371280.258210746X-RAY DIFFRACTION99
2.33-2.40.30971600.248610824X-RAY DIFFRACTION99
2.4-2.490.26791230.2410794X-RAY DIFFRACTION99
2.49-2.590.31611440.239910800X-RAY DIFFRACTION100
2.59-2.710.28921440.237510806X-RAY DIFFRACTION100
2.71-2.850.30051380.244210850X-RAY DIFFRACTION100
2.85-3.030.34321410.239110873X-RAY DIFFRACTION100
3.03-3.260.27041460.228510848X-RAY DIFFRACTION100
3.26-3.590.29161490.20610917X-RAY DIFFRACTION100
3.59-4.10.21121450.177210901X-RAY DIFFRACTION100
4.1-5.150.18781440.157510977X-RAY DIFFRACTION100
5.15-19.880.22941490.181311097X-RAY DIFFRACTION100

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