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- PDB-2cnl: Crystal structures of caspase-3 in complex with aza-peptide epoxi... -

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Basic information

Entry
Database: PDB / ID: 2cnl
TitleCrystal structures of caspase-3 in complex with aza-peptide epoxide inhibitors.
Components
  • AZA-PEPTIDE EPOXIDE
  • CASPASE-3 SUBUNIT P12
  • CASPASE-3 SUBUNIT P17
KeywordsHYDROLASE/HYDROLASE INHIBITOR / THIOL PROTEASE / PHOSPHORYLATION / CYSTEINE-PROTEASE / PROTEASE-INHIBITOR COMPLEX / ICE / YAMA / CPP32 / CLAN CD / PROTEASE / EPOXIDES / TETRAMER / APOPTOSIS / AZA-PEPTIDE / EPOXYSUCCINYL / AZA-ASP / ZYMOGEN / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
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
CBZ-ASP-GLU-VAL-azaASP-EP-CO-NH-CH2PH / Caspase-3
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
SYNTHETIC CONSTRUCT (others)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 1.67 Å
AuthorsGanesan, R. / Jelakovic, S. / Campbell, A.J. / Li, Z.Z. / Asgian, J.L. / Grutter, M.G. / Powers, J.C.
CitationJournal: Biochemistry / Year: 2006
Title: Exploring the S4 and S1 Prime Subsite Specificities in Caspase-3 with Aza-Peptide Epoxide Inhibitors
Authors: Ganesan, R. / Jelakovic, S. / Campbell, A.J. / Li, Z.Z. / Asgian, J.L. / Powers, J.C. / Grutter, M.G.
History
DepositionMay 22, 2006Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 22, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.2Nov 30, 2012Group: Other
Revision 1.3Feb 8, 2017Group: Source and taxonomy / Structure summary
Revision 1.4Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Other
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_dist_value / _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_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CASPASE-3 SUBUNIT P17
B: CASPASE-3 SUBUNIT P12
I: AZA-PEPTIDE EPOXIDE


Theoretical massNumber of molelcules
Total (without water)29,4133
Polymers29,4133
Non-polymers00
Water6,503361
1
A: CASPASE-3 SUBUNIT P17
B: CASPASE-3 SUBUNIT P12
I: AZA-PEPTIDE EPOXIDE

A: CASPASE-3 SUBUNIT P17
B: CASPASE-3 SUBUNIT P12
I: AZA-PEPTIDE EPOXIDE


Theoretical massNumber of molelcules
Total (without water)58,8266
Polymers58,8266
Non-polymers00
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_656-x+1,y,-z+11
MethodPQS
Unit cell
Length a, b, c (Å)67.694, 83.963, 96.271
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

#1: Protein CASPASE-3 SUBUNIT P17 / CASP-3 / APOPAIN / CYSTEINE PROTEASE CPP32 / YAMA PROTEIN / CPP- 32 / SREBP CLEAVAGE ACTIVITY 1 / SCA-1


Mass: 16639.902 Da / Num. of mol.: 1 / Fragment: ALPHA SUBUNIT, RESIDUES 29-175
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PET11D (NOVAGEN) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) (STRATAGENE)
References: UniProt: P42574, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Protein CASPASE-3 SUBUNIT P12 / CASP-3 / APOPAIN / CYSTEINE PROTEASE CPP32 / YAMA PROTEIN / CPP- 32 / SREBP CLEAVAGE ACTIVITY 1 / SCA-1


Mass: 11981.682 Da / Num. of mol.: 1 / Fragment: BETA SUBUNIT, RESIDUES 176-277
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P42574
#3: Protein/peptide AZA-PEPTIDE EPOXIDE


Type: Peptide-like / Class: Enzyme inhibitor / Mass: 791.201 Da / Num. of mol.: 1 / Fragment: CBZ-ASP-GLU-VAL-AASP-EP-CO-NH-CH2PH / Source method: obtained synthetically / Source: (synth.) SYNTHETIC CONSTRUCT (others) / References: CBZ-ASP-GLU-VAL-azaASP-EP-CO-NH-CH2PH
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 361 / Source method: isolated from a natural source / Formula: H2O
Compound detailsTHE STARTING INHIBITOR COMPOUND AZA-PEPTIDE EPOXIDE CBZ-DEV-AZAASP- EPCO-NHCH2PH BINDS TO ACTIVE ...THE STARTING INHIBITOR COMPOUND AZA-PEPTIDE EPOXIDE CBZ-DEV-AZAASP- EPCO-NHCH2PH BINDS TO ACTIVE SITE CYSTEINE CYS 163 RESULTING IN A COVALENT THIOETHER BOND AND OXIRANE RING OPENING. THE INHIBITOR IS INVOLVED IN THE ACTIVATION CASCADE OF CASPASES RESPONSIBLE FOR APOPTOSIS EXECUTION.

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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: 2.34 Å3/Da / Density % sol: 45.36 %
Crystal growpH: 4.75 / Details: PEG6000, 100 MM SODIUM CITRATE PH 4.75

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: ENRAF-NONIUS FR591 / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Jan 21, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.67→20 Å / Num. obs: 31449 / % possible obs: 98.1 % / Observed criterion σ(I): 3.8 / Redundancy: 4.4 % / Biso Wilson estimate: 22.9 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 17.3
Reflection shellResolution: 1.67→1.76 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.33 / Mean I/σ(I) obs: 3.8 / % possible all: 93.4

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Processing

Software
NameVersionClassification
CNS1.1refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: OTHER / Resolution: 1.67→19.85 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 1523798.97 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
Details: CLONING ARTIFACT. ADDITIONAL AMINO ACID CHAIN B, ALA 175
RfactorNum. reflection% reflectionSelection details
Rfree0.217 3148 10 %RANDOM
Rwork0.188 ---
obs0.188 31449 97.9 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 63.071 Å2 / ksol: 0.354542 e/Å3
Displacement parametersBiso mean: 21.9 Å2
Baniso -1Baniso -2Baniso -3
1-3.96 Å20 Å20 Å2
2--0.28 Å20 Å2
3----4.24 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.22 Å0.18 Å
Luzzati d res low-5 Å
Luzzati sigma a0.16 Å0.14 Å
Refinement stepCycle: LAST / Resolution: 1.67→19.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2059 0 0 361 2420
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d23.2
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.65
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.081.5
X-RAY DIFFRACTIONc_mcangle_it1.642
X-RAY DIFFRACTIONc_scbond_it2.122
X-RAY DIFFRACTIONc_scangle_it3.012.5
LS refinement shellResolution: 1.67→1.77 Å / Rfactor Rfree error: 0.017 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.377 489 10 %
Rwork0.344 4398 -
obs--91.9 %
Xplor fileSerial no: 1 / Param file: PROTEIN_REP.PARAM / Topol file: PROTEIN.TOP

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