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- PDB-1rhu: CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-3 WITH A 5,6,7 TRICYC... -

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Basic information

Entry
Database: PDB / ID: 1rhu
TitleCRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-3 WITH A 5,6,7 TRICYCLIC PEPTIDOMIMETIC INHIBITOR
Components(Caspase-3) x 2
KeywordsHYDROLASE / CYSTEINE PROTEASE / CASPASE-3 / APOPAIN / CPP32 / YAMA / COMPLEX (PROTEASE-INHIBITOR)
Function / homology
Function and homology information


caspase-3 / Stimulation of the cell death response by PAK-2p34 / phospholipase A2 activator activity / anterior neural tube closure / intrinsic apoptotic signaling pathway in response to osmotic stress / leukocyte apoptotic process / positive regulation of pyroptotic inflammatory response / glial cell apoptotic process / NADE modulates death signalling / luteolysis ...caspase-3 / Stimulation of the cell death response by PAK-2p34 / phospholipase A2 activator activity / anterior neural tube closure / intrinsic apoptotic signaling pathway in response to osmotic stress / leukocyte apoptotic process / positive regulation of pyroptotic inflammatory response / glial cell apoptotic process / NADE modulates death signalling / luteolysis / response to cobalt ion / cysteine-type endopeptidase activity involved in apoptotic signaling pathway / death-inducing signaling complex / cyclin-dependent protein serine/threonine kinase inhibitor activity / cellular response to staurosporine / Apoptosis induced DNA fragmentation / cysteine-type endopeptidase activity involved in execution phase of apoptosis / Caspase activation via Dependence Receptors in the absence of ligand / Apoptotic cleavage of cell adhesion proteins / death receptor binding / SMAC, XIAP-regulated apoptotic response / Activation of caspases through apoptosome-mediated cleavage / axonal fasciculation / Signaling by Hippo / cysteine-type endopeptidase activity involved in apoptotic process / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / fibroblast apoptotic process / execution phase of apoptosis / negative regulation of cytokine production / epithelial cell apoptotic process / platelet formation / Other interleukin signaling / positive regulation of amyloid-beta formation / Apoptotic cleavage of cellular proteins / pyroptotic inflammatory response / negative regulation of B cell proliferation / T cell homeostasis / negative regulation of activated T cell proliferation / B cell homeostasis / neurotrophin TRK receptor signaling pathway / protein maturation / negative regulation of cell cycle / response to X-ray / Caspase-mediated cleavage of cytoskeletal proteins / response to amino acid / cell fate commitment / regulation of macroautophagy / response to tumor necrosis factor / Pyroptosis / response to glucose / response to UV / response to glucocorticoid / keratinocyte differentiation / enzyme activator activity / striated muscle cell differentiation / Degradation of the extracellular matrix / intrinsic apoptotic signaling pathway / erythrocyte differentiation / hippocampus development / apoptotic signaling pathway / sensory perception of sound / response to nicotine / protein catabolic process / regulation of protein stability / response to hydrogen peroxide / neuron differentiation / protein processing / response to wounding / positive regulation of neuron apoptotic process / response to estradiol / peptidase activity / heart development / neuron apoptotic process / protease binding / response to lipopolysaccharide / aspartic-type endopeptidase activity / learning or memory / response to hypoxia / response to xenobiotic stimulus / cysteine-type endopeptidase activity / neuronal cell body / apoptotic process / DNA damage response / protein-containing complex binding / proteolysis / nucleoplasm / nucleus / cytoplasm / cytosol
Similarity search - Function
Caspase-like / Rossmann fold - #1460 / Peptidase family C14A, His active site / Caspase family histidine active site. / Peptidase C14, caspase non-catalytic subunit p10 / Peptidase family C14A, cysteine active site / Caspase family cysteine active site. / Caspase family p10 domain profile. / Peptidase C14A, caspase catalytic domain / Caspase, interleukin-1 beta converting enzyme (ICE) homologues ...Caspase-like / Rossmann fold - #1460 / Peptidase family C14A, His active site / Caspase family histidine active site. / Peptidase C14, caspase non-catalytic subunit p10 / Peptidase family C14A, cysteine active site / Caspase family cysteine active site. / Caspase family p10 domain profile. / Peptidase C14A, caspase catalytic domain / Caspase, interleukin-1 beta converting enzyme (ICE) homologues / Peptidase C14, p20 domain / Caspase family p20 domain profile. / : / Caspase domain / Caspase-like domain superfamily / Alpha-Beta Plaits / Rossmann fold / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-3CY / Caspase-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.51 Å
AuthorsBecker, J.W. / Rotonda, J. / Soisson, S.M.
CitationJournal: J.Med.Chem. / Year: 2004
Title: Reducing the Peptidyl Features of Caspase-3 Inhibitors: A Structural Analysis.
Authors: Becker, J.W. / Rotonda, J. / Soisson, S.M. / Aspiotis, R. / Bayly, C. / Francoeur, S. / Gallant, M. / Garcia-Calvo, M. / Giroux, A. / Grimm, E. / Han, Y. / McKay, D. / Nicholson, D.W. / ...Authors: Becker, J.W. / Rotonda, J. / Soisson, S.M. / Aspiotis, R. / Bayly, C. / Francoeur, S. / Gallant, M. / Garcia-Calvo, M. / Giroux, A. / Grimm, E. / Han, Y. / McKay, D. / Nicholson, D.W. / Peterson, E. / Renaud, J. / Roy, S. / Thornberry, N. / Zamboni, R.
History
DepositionNov 14, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 11, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Derived calculations / Version format compliance
Revision 1.3Oct 11, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.4Dec 21, 2022Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Sep 20, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Caspase-3
B: Caspase-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,1893
Polymers28,5512
Non-polymers6391
Water1,78399
1
A: Caspase-3
B: Caspase-3
hetero molecules

A: Caspase-3
B: Caspase-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,3786
Polymers57,1014
Non-polymers1,2772
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_755-x+2,-y,z1
Buried area15380 Å2
ΔGint-74 kcal/mol
Surface area17220 Å2
MethodPISA, PQS
Unit cell
Length a, b, c (Å)69.500, 98.000, 44.000
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
DetailsThe second part of the biological assembly is generated by the two-fold axis: 2-x, -y, z

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Components

#1: Protein Caspase-3 / Cysteine protease CPP32 / Yama protein / CPP-32 / Apopain / CASP-3 / SREBP cleavage activity 1 / SCA-1


Mass: 16639.902 Da / Num. of mol.: 1 / Fragment: P17 SUBUNIT
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP3, CPP32 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P42574, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Protein Caspase-3 / Cysteine protease CPP32 / Yama protein / CPP-32 / Apopain / CASP-3 / SREBP cleavage activity 1 / SCA-1


Mass: 11910.604 Da / Num. of mol.: 1 / Fragment: P12 SUBUNIT
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP3, CPP32 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P42574, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#3: Chemical ChemComp-3CY / (3S)-3-[({(2S)-5-[(N-ACETYL-L-ALPHA-ASPARTYL)AMINO]-4-OXO-1,2,4,5,6,7-HEXAHYDROAZEPINO[3,2,1-HI]INDOL-2-YL}CARBONYL)AMINO]-5-(BENZYLSULFANYL)-4-OXOPENTANOIC ACID


Mass: 638.688 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H34N4O9S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 99 / Source method: isolated from a natural source / Formula: H2O

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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: 2.62 Å3/Da / Density % sol: 53.12 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 3.6
Details: 0.5% PEG-6000, 100 mM citrate, 3 mM NaN(3), pH 3.60, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 293 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.54178 Å
DetectorType: SIEMENS / Detector: AREA DETECTOR / Date: Apr 3, 1999
RadiationMonochromator: Graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.513→49 Å / Num. all: 10801 / Num. obs: 9500 / % possible obs: 88 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.085 % / Biso Wilson estimate: 18.1 Å2 / Rmerge(I) obs: 0.057 / Net I/σ(I): 22.17
Reflection shellResolution: 2.513→2.603 Å / Redundancy: 1.408 % / Rmerge(I) obs: 0.193 / Mean I/σ(I) obs: 4.34 / Num. unique all: 265 / % possible all: 25

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Processing

Software
NameVersionClassification
CNX2002refinement
X-GENdata reduction
SAINTV. 4.050data scaling
X-PLORphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Protein part of 1PAU.pdb

1pau


Resolution: 2.51→49 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 47703.24 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.212 916 10.4 %RANDOM
Rwork0.166 ---
all-8836 --
obs-8836 81.5 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 21.3842 Å2 / ksol: 0.290242 e/Å3
Displacement parametersBiso mean: 29.4 Å2
Baniso -1Baniso -2Baniso -3
1-6.26 Å20 Å20 Å2
2---7.49 Å20 Å2
3---1.23 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.32 Å0.24 Å
Luzzati d res low-5 Å
Luzzati sigma a0.34 Å0.29 Å
Refinement stepCycle: LAST / Resolution: 2.51→49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1870 0 45 99 2014
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_dihedral_angle_d23.3
X-RAY DIFFRACTIONc_improper_angle_d0.76
X-RAY DIFFRACTIONc_mcbond_it1.221.5
X-RAY DIFFRACTIONc_mcangle_it2.042
X-RAY DIFFRACTIONc_scbond_it2.052
X-RAY DIFFRACTIONc_scangle_it3.22.5
LS refinement shellResolution: 2.5→2.66 Å / Rfactor Rfree error: 0.035 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.242 49 8.6 %
Rwork0.211 524 -
obs-515 32 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARWATER.TOP
X-RAY DIFFRACTION3ION.PARAMION.TOP
X-RAY DIFFRACTION4TRI.PARTRI.TOP

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