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

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Basic information

Entry
Database: PDB / ID: 2cdr
TitleCrystal structures of caspase-3 in complex with aza-peptide epoxide inhibitors.
Components
  • AZA-PEPTIDE EXPOXIDE
  • CASPASE-3 SUBUNIT P12Caspase 3
  • CASPASE-3 SUBUNIT P17Caspase 3
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HYDROLASE-HYDROLASE INHIBITOR COMPLEX / APOPTOSIS / PROTEASE-INHIBITOR COMPLEX / CYSTEINE-PROTEASE / HYDROLASE / ICE / TETRAMER / THIOL PROTEASE / ZYMOGEN / CPP32 / YAMA / AZA-PEPTIDE / EPOXYSUCCINYL / AZA-ASP / CLAN CD / EPOXIDES
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 / Apoptotic cleavage of cell adhesion proteins / cysteine-type endopeptidase activity involved in execution phase of apoptosis / Caspase activation via Dependence Receptors in the absence of ligand / death receptor binding / SMAC, XIAP-regulated apoptotic response / axonal fasciculation / Activation of caspases through apoptosome-mediated cleavage / Signaling by Hippo / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / cysteine-type endopeptidase activity involved in apoptotic process / 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 / pyroptotic inflammatory response / Apoptotic cleavage of cellular proteins / negative regulation of B cell proliferation / T cell homeostasis / negative regulation of activated T cell proliferation / neurotrophin TRK receptor signaling pathway / B cell homeostasis / protein maturation / negative regulation of cell cycle / response to X-ray / Caspase-mediated cleavage of cytoskeletal proteins / regulation of macroautophagy / response to amino acid / cell fate commitment / Pyroptosis / response to tumor necrosis factor / response to glucose / response to UV / response to glucocorticoid / keratinocyte differentiation / striated muscle cell differentiation / Degradation of the extracellular matrix / intrinsic apoptotic signaling pathway / erythrocyte differentiation / response to nicotine / apoptotic signaling pathway / hippocampus development / sensory perception of sound / protein catabolic process / regulation of protein stability / response to hydrogen peroxide / protein processing / neuron differentiation / response to wounding / positive regulation of neuron apoptotic process / response to estradiol / heart development / peptidase activity / neuron apoptotic process / protease binding / response to lipopolysaccharide / aspartic-type endopeptidase activity / response to hypoxia / learning or memory / response to xenobiotic stimulus / positive regulation of apoptotic process / cysteine-type endopeptidase activity / neuronal cell body / apoptotic process / DNA damage response / protein-containing complex binding / proteolysis / nucleoplasm / nucleus / cytosol / cytoplasm
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-N(CH2PH)2 / Caspase-3
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 1.7 Å
AuthorsGanesan, R. / Jelakovic, S. / Campbell, A.J. / Li, Z.Z. / Asgian, J.L. / Powers, J.C. / Gruetter, M.G.
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
DepositionJan 27, 2006Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 20, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Atomic model ...Advisory / Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.2Jul 20, 2011Group: Other
Revision 1.3Nov 30, 2012Group: Other
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_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

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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 EXPOXIDE


Theoretical massNumber of molelcules
Total (without water)29,5033
Polymers29,5033
Non-polymers00
Water6,539363
1
A: CASPASE-3 SUBUNIT P17
B: CASPASE-3 SUBUNIT P12
I: AZA-PEPTIDE EXPOXIDE

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

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

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


Theoretical massNumber of molelcules
Total (without water)118,01212
Polymers118,01212
Non-polymers00
Water21612
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_656-x+1,y,-z+11
crystal symmetry operation2_665-x+1,-y+1,z1
crystal symmetry operation4_566x,-y+1,-z+11
Buried area40410 Å2
ΔGint-134.7 kcal/mol
Surface area35870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.471, 83.781, 96.251
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 / Caspase 3 / CASP-3 / APOPAIN / CYSTEINE PROTEASE CPP32 / CPP-32 / YAMA PROTEIN / 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)
References: UniProt: P42574, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Protein CASPASE-3 SUBUNIT P12 / Caspase 3 / CASP-3 / APOPAIN / CYSTEINE PROTEASE CPP32 / CPP-32 / YAMA PROTEIN / 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) / Plasmid: PET11D (NOVAGEN) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P42574, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#3: Protein/peptide AZA-PEPTIDE EXPOXIDE


Type: Peptide-like / Class: Enzyme inhibitor / Mass: 881.324 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: CBZ-ASP-GLU-VAL-AASP-EP-CO-N(CH2PH)2 / Source: (synth.) HOMO SAPIENS (human) / References: CBZ-ASP-GLU-VAL-azaASP-EP-CO-N(CH2PH)2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 363 / Source method: isolated from a natural source / Formula: H2O
Compound detailsTHE STARTING INHIBITOR COMPOUND AZA-PEPTIDE EPOXIDE CBZ-DEV-AZAASP- EPCO-N(CH2PH)2 BINDS TO ACTIVE ...THE STARTING INHIBITOR COMPOUND AZA-PEPTIDE EPOXIDE CBZ-DEV-AZAASP- EPCO-N(CH2PH)2 BINDS TO ACTIVE SITE CYSTEINE CYS 163 RESULTING IN A COVALENT THIOETHER BOND AND OXIRANE RING OPENING.

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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: 2.27 Å3/Da / Density % sol: 45.8 %
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: 1.54
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Sep 30, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.7→20 Å / Num. obs: 28860 / % possible obs: 97.7 % / Observed criterion σ(I): 3 / Redundancy: 4.1 % / Biso Wilson estimate: 19.2 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 18.8
Reflection shellResolution: 1.7→1.79 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.3 / Mean I/σ(I) obs: 3.9 / % possible all: 93

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Processing

Software
NameVersionClassification
CNS1.1refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: OTHER / Resolution: 1.7→19.49 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 1635499.42 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.204 2876 10 %RANDOM
Rwork0.177 ---
obs0.177 28860 97.9 %-
Displacement parametersBiso mean: 21.6 Å2
Baniso -1Baniso -2Baniso -3
1-4.57 Å20 Å20 Å2
2--1.52 Å20 Å2
3----6.09 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.2 Å0.17 Å
Luzzati d res low-5 Å
Luzzati sigma a0.2 Å0.19 Å
Refinement stepCycle: LAST / Resolution: 1.7→19.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2066 0 0 363 2429
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_d23.1
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.64
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.11.5
X-RAY DIFFRACTIONc_mcangle_it1.652
X-RAY DIFFRACTIONc_scbond_it2.082
X-RAY DIFFRACTIONc_scangle_it2.922.5
LS refinement shellResolution: 1.7→1.81 Å / Rfactor Rfree error: 0.015 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.32 456 10 %
Rwork0.32 4083 -
obs--93.7 %

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