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- PDB-2c2o: Crystal structures of caspase-3 in complex with aza-peptide Micha... -

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Basic information

Entry
Database: PDB / ID: 2c2o
TitleCrystal structures of caspase-3 in complex with aza-peptide Michael acceptor inhibitors.
Components
  • AZA-PEPTIDE INHIBITOR (5S, 8R, 11S)-14-{4-[BENZYL(METHYL) AMINO]-4-OXOBUTANOYL}-8-(2-CARBOXYETHYL)-5-(CARBOXYMETHYL)-11-(1-METHYLETHYL)-3,6,9,12-TETRAOXO-1-PHENYL-2-OXA-4,7,10,13,14-PENTAAZAHEXADECAN-16-OIC ACID
  • CASPASE-3 SUBUNIT P12Caspase 3
  • CASPASE-3 SUBUNIT P17Caspase 3
KeywordsHYDROLASE/HYDROLASE INHIBITOR / APOPTOSIS / HYDROLASE-HYDROLASE INHIBITOR COMPLEX / CYSTEINE-PROTEASE / ICE / TETRAMER / THIOL PROTEASE / ZYMOGEN / CPP32 / YAMA / AZA-PEPTIDE / MICHAEL ACCEPTOR / AZA-ASP / CLAN CD
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-AAsp-CHCH-CON(CH3)CH2Ph / Caspase-3
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
SYNTHETIC CONSTRUCT (others)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 2.45 Å
AuthorsGanesan, R. / Jelakovic, S. / Ekici, O.D. / Li, Z.Z. / James, K.E. / Asgian, J.L. / Campbell, A. / Mikolajczyk, J. / Salvesen, G.S. / Gruetter, M.G. / Powers, J.C.
CitationJournal: J.Med.Chem. / Year: 2006
Title: Design, Synthesis, and Evaluation of Aza-Peptide Michael Acceptors as Selective and Potent Inhibitors of Caspases-2, -3, -6, -7, -8, -9, and - 10.
Authors: Ekici, O.D. / Li, Z.Z. / Campbell, A.J. / James, K.E. / Asgian, J.L. / Mikolajczyk, J. / Salvesen, G.S. / Ganesan, R. / Jelakovic, S. / Grutter, M.G. / Powers, J.C.
History
DepositionSep 29, 2005Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 20, 2006Provider: 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
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 / pdbx_validate_main_chain_plane / pdbx_validate_rmsd_angle / 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
C: AZA-PEPTIDE INHIBITOR (5S, 8R, 11S)-14-{4-[BENZYL(METHYL) AMINO]-4-OXOBUTANOYL}-8-(2-CARBOXYETHYL)-5-(CARBOXYMETHYL)-11-(1-METHYLETHYL)-3,6,9,12-TETRAOXO-1-PHENYL-2-OXA-4,7,10,13,14-PENTAAZAHEXADECAN-16-OIC ACID


Theoretical massNumber of molelcules
Total (without water)29,4113
Polymers29,4113
Non-polymers00
Water2,684149
1
A: CASPASE-3 SUBUNIT P17
B: CASPASE-3 SUBUNIT P12
C: AZA-PEPTIDE INHIBITOR (5S, 8R, 11S)-14-{4-[BENZYL(METHYL) AMINO]-4-OXOBUTANOYL}-8-(2-CARBOXYETHYL)-5-(CARBOXYMETHYL)-11-(1-METHYLETHYL)-3,6,9,12-TETRAOXO-1-PHENYL-2-OXA-4,7,10,13,14-PENTAAZAHEXADECAN-16-OIC ACID

A: CASPASE-3 SUBUNIT P17
B: CASPASE-3 SUBUNIT P12
C: AZA-PEPTIDE INHIBITOR (5S, 8R, 11S)-14-{4-[BENZYL(METHYL) AMINO]-4-OXOBUTANOYL}-8-(2-CARBOXYETHYL)-5-(CARBOXYMETHYL)-11-(1-METHYLETHYL)-3,6,9,12-TETRAOXO-1-PHENYL-2-OXA-4,7,10,13,14-PENTAAZAHEXADECAN-16-OIC ACID


Theoretical massNumber of molelcules
Total (without water)58,8226
Polymers58,8226
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)66.402, 83.491, 96.356
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


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 / Caspase 3


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, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#3: Protein/peptide AZA-PEPTIDE INHIBITOR (5S, 8R, 11S)-14-{4-[BENZYL(METHYL) AMINO]-4-OXOBUTANOYL}-8-(2-CARBOXYETHYL)-5-(CARBOXYMETHYL)-11-(1-METHYLETHYL)-3,6,9,12-TETRAOXO-1-PHENYL-2-OXA-4,7,10,13,14-PENTAAZAHEXADECAN-16-OIC ACID


Type: Peptide-like / Class: Inhibitor / Mass: 789.228 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) SYNTHETIC CONSTRUCT (others) / References: Cbz-Asp-Glu-Val-AAsp-CHCH-CON(CH3)CH2Ph
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 149 / Source method: isolated from a natural source / Formula: H2O
Compound detailsTHE INITIAL LIGAND USED IN THE EXPERIMENT WAS CBZ-DEVAD-CH=CH- CON(CH3)BZL, INDICATED AS 18O IN THE ...THE INITIAL LIGAND USED IN THE EXPERIMENT WAS CBZ-DEVAD-CH=CH- CON(CH3)BZL, INDICATED AS 18O IN THE PRIMARY PUBLICATION. UPON REACTION, THE DOUBLE BOND OPENED UP AND FORMED A COVALENT BOND BETWEEN ATOM C10 OF RESIDUE MX3 5 OF CHAIN C AND ATOM SG OF CYS 163 OF CHAIN A.

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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: 2.28 Å3/Da / Density % sol: 46 %
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 4, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.45→20 Å / Num. obs: 10094 / % possible obs: 99.2 % / Observed criterion σ(I): 0 / Redundancy: 5.8 % / Biso Wilson estimate: 22 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 19.6
Reflection shellResolution: 2.45→2.58 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.24 / Mean I/σ(I) obs: 7 / % possible all: 95.8

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Processing

Software
NameVersionClassification
CNS1.1refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: OTHER / Resolution: 2.45→19.55 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 1590597.21 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
Details: MISSING RESIDUE CHAIN A, ASP 175 CLONING ARTIFACT ADDITIONAL AMINO ACID CHAIN B, ALA 175
RfactorNum. reflection% reflectionSelection details
Rfree0.215 1040 10.3 %RANDOM
Rwork0.168 ---
obs0.168 10094 99.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 37.18 Å2 / ksol: 0.36 e/Å3
Displacement parametersBiso mean: 21 Å2
Baniso -1Baniso -2Baniso -3
1-1.05 Å20 Å20 Å2
2--4.11 Å20 Å2
3----5.15 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.29 Å0.21 Å
Luzzati d res low-5 Å
Luzzati sigma a0.3 Å0.21 Å
Refinement stepCycle: LAST / Resolution: 2.45→19.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2051 0 0 149 2200
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
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_deg1.2
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d22.9
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.62
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.21.5
X-RAY DIFFRACTIONc_mcangle_it1.932
X-RAY DIFFRACTIONc_scbond_it2.162
X-RAY DIFFRACTIONc_scangle_it3.072.5
LS refinement shellResolution: 2.45→2.6 Å / Rfactor Rfree error: 0.022 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.263 144 9 %
Rwork0.202 1457 -
obs--96.2 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER.PARAM

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