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- PDB-2h65: Crystal strusture of caspase-3 with inhibitor Ac-VDVAD-Cho -

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Basic information

Entry
Database: PDB / ID: 2h65
TitleCrystal strusture of caspase-3 with inhibitor Ac-VDVAD-Cho
Components
  • Ac-VDVAD-Cho
  • caspase-3, p12 subunit
  • caspase-3, p17 subunit
KeywordsHYDROLASE/HYDROLASE INHIBITOR / ENZYME CATALYSIS / CYSTEINE PROTEASE / APOPTOSIS / INDUCED FIT / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


caspase-3 / phospholipase A2 activator activity / Stimulation of the cell death response by PAK-2p34 / 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 / phospholipase A2 activator activity / Stimulation of the cell death response by PAK-2p34 / 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 / cellular response to staurosporine / cyclin-dependent protein serine/threonine kinase inhibitor activity / death-inducing signaling complex / Apoptosis induced DNA fragmentation / Apoptotic cleavage of cell adhesion proteins / Caspase activation via Dependence Receptors in the absence of ligand / SMAC, XIAP-regulated apoptotic response / Activation of caspases through apoptosome-mediated cleavage / Signaling by Hippo / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / axonal fasciculation / regulation of synaptic vesicle cycle / death receptor binding / fibroblast apoptotic process / epithelial cell apoptotic process / platelet formation / Other interleukin signaling / response to anesthetic / execution phase of apoptosis / negative regulation of cytokine production / positive regulation of amyloid-beta formation / Apoptotic cleavage of cellular proteins / negative regulation of B cell proliferation / pyroptotic inflammatory response / neurotrophin TRK receptor signaling pathway / negative regulation of activated T cell proliferation / negative regulation of cell cycle / response to tumor necrosis factor / T cell homeostasis / B cell homeostasis / Pyroptosis / cell fate commitment / regulation of macroautophagy / Caspase-mediated cleavage of cytoskeletal proteins / response to X-ray / response to amino acid / response to glucose / response to UV / keratinocyte differentiation / Degradation of the extracellular matrix / striated muscle cell differentiation / intrinsic apoptotic signaling pathway / response to glucocorticoid / protein maturation / erythrocyte differentiation / response to nicotine / hippocampus development / apoptotic signaling pathway / enzyme activator activity / protein catabolic process / response to hydrogen peroxide / sensory perception of sound / protein processing / regulation of protein stability / response to wounding / neuron differentiation / response to estradiol / peptidase activity / positive regulation of neuron apoptotic process / heart development / protease binding / neuron apoptotic process / response to lipopolysaccharide / aspartic-type endopeptidase activity / learning or memory / response to hypoxia / postsynaptic density / response to xenobiotic stimulus / cysteine-type endopeptidase activity / neuronal cell body / apoptotic process / DNA damage response / protein-containing complex binding / glutamatergic synapse / proteolysis / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
Caspase-like / Rossmann fold - #1460 / Peptidase C14 family / 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-like / Rossmann fold - #1460 / Peptidase C14 family / 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
Caspase-2 Inhibitor; Ac-VDVAD-Cho / Caspase-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsFang, B. / Boross, P.I. / Tozser, J. / Weber, I.T.
CitationJournal: J.Mol.Biol. / Year: 2006
Title: Structural and kinetic analysis of caspase-3 reveals role for s5 binding site in substrate recognition
Authors: Fang, B. / Boross, P.I. / Tozser, J. / Weber, I.T.
History
DepositionMay 30, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 19, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.3Dec 12, 2012Group: Other
Revision 1.4Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ref_seq_dif
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_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details
Revision 1.5Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: caspase-3, p17 subunit
B: caspase-3, p12 subunit
C: caspase-3, p17 subunit
D: caspase-3, p12 subunit
E: Ac-VDVAD-Cho
F: Ac-VDVAD-Cho


Theoretical massNumber of molelcules
Total (without water)56,6256
Polymers56,6256
Non-polymers00
Water1,54986
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15880 Å2
ΔGint-84 kcal/mol
Surface area17340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.890, 67.400, 93.490
Angle α, β, γ (deg.)90.000, 100.800, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein caspase-3, p17 subunit / E.C.3.4.22.- / CASP-3 / Apopain / Cysteine protease CPP32 / Yama protein / CPP-32 / SREBP cleavage activity 1 / SCA-1


Mass: 16524.814 Da / Num. of mol.: 2 / Fragment: residues 29-174
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP3, CPP32 / Plasmid: pET23b / Species (production host): Escherichia coli / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21
References: UniProt: P42574, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Protein caspase-3, p12 subunit / E.C.3.4.22.-


Mass: 11257.953 Da / Num. of mol.: 2 / Fragment: residues 184-277
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP3, CPP32 / Plasmid: pET23b / Species (production host): Escherichia coli / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21
References: UniProt: P42574, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#3: Protein/peptide Ac-VDVAD-Cho


Type: Peptide-like / Class: Inhibitor / Mass: 529.584 Da / Num. of mol.: 2 / Source method: obtained synthetically / References: Caspase-2 Inhibitor; Ac-VDVAD-Cho
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 86 / Source method: isolated from a natural source / Formula: H2O
Compound detailsTHE INHIBITOR IS COVALENTLY CONNECTED TO CYS OF THE ENZYME TO FORM A HEMITHIOKETAL

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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: 2.73 Å3/Da / Density % sol: 54.89 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 100 mM sodium citrate, 5% glycerol, 10 mM dithiothreitol and 14-18% PEG6000, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Mar 15, 2005
RadiationMonochromator: Si 220 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. all: 34990 / Num. obs: 34990 / % possible obs: 97.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.2 % / Biso Wilson estimate: 24.5 Å2 / Rmerge(I) obs: 0.088 / Net I/σ(I): 11
Reflection shellResolution: 2.2→2.3 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.297 / Mean I/σ(I) obs: 4 / % possible all: 98.1

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Processing

Software
NameClassification
MADCCDdata collection
HKL-2000data reduction
AMoREphasing
CNSrefinement
MADCCDdata reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1CP3

1cp3


Resolution: 2.3→10 Å / FOM work R set: 0.833 / Isotropic thermal model: Isotropic
Cross valid method: maximum likelihood target using amplitudes
σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.246 1265 4.7 %RANDOM
Rwork0.209 ---
all0.208 25859 --
obs0.198 23763 96 %-
Solvent computationBsol: 40.134 Å2
Displacement parametersBiso mean: 29.896 Å2
Baniso -1Baniso -2Baniso -3
1--2.128 Å20 Å28.156 Å2
2---4.882 Å20 Å2
3---7.01 Å2
Refinement stepCycle: LAST / Resolution: 2.3→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3852 0 0 86 3938
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_d1.266
X-RAY DIFFRACTIONc_mcbond_it1.4891.5
X-RAY DIFFRACTIONc_scbond_it2.4932
X-RAY DIFFRACTIONc_mcangle_it2.4852
X-RAY DIFFRACTIONc_scangle_it3.812.5
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 25

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection obs
2.3-2.330.284540.27927981
2.33-2.360.295650.25885950
2.36-2.40.243470.245927974
2.4-2.440.279510.251898949
2.44-2.480.289440.2649701014
2.48-2.520.289510.2539611012
2.52-2.560.276430.2419691012
2.56-2.610.342380.2589791017
2.61-2.660.328470.26951998
2.66-2.720.409460.2679891035
2.72-2.780.313500.249811031
2.78-2.850.312430.2579771020
2.85-2.920.287530.24110391092
2.92-3.010.259450.2249721017
3.01-3.10.268500.20710171067
3.1-3.210.259520.2389981050
3.21-3.330.245470.20510381085
3.33-3.480.201460.1910021048
3.48-3.650.212610.1810051066
3.65-3.870.201590.18210181077
3.87-4.150.206580.17810111069
4.15-4.530.156420.16210261068
4.53-5.110.193500.16910151065
5.11-6.170.291630.21310191082
6.17-100.216600.18510201080
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2CNS_TOPPAR:water_rep.paramCNS_TOPPAR:water.top

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