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- PDB-2dko: Extended substrate recognition in caspase-3 revealed by high reso... -

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Basic information

Entry
Database: PDB / ID: 2dko
TitleExtended substrate recognition in caspase-3 revealed by high resolution X-ray structure analysis
Components
  • (Caspase-3Caspase 3) x 2
  • PHQ-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE
KeywordsHYDROLASE/HYDROLASE INHIBITOR / LOW BARRIER HYDROGEN BOND / CASPASE / DRUG DESIGN / RADIATION DAMAGE / TETRAHEDRAL INTERMEDIATE / PROTEASE / 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 / 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
N-[(benzyloxy)carbonyl]-L-alpha-aspartyl-L-alpha-glutamyl-N-[(1S)-1-(carboxymethyl)-3-chloro-2-oxopropyl]-L-valinamide / Caspase-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.06 Å
AuthorsMittl, P.R.E. / Ganesan, R. / Jelakovic, S. / Grutter, M.G.
CitationJournal: J.Mol.Biol. / Year: 2006
Title: Extended Substrate Recognition in Caspase-3 Revealed by High Resolution X-ray Structure Analysis
Authors: Ganesan, R. / Mittl, P.R.E. / Jelakovic, S. / Grutter, M.G.
History
DepositionApr 12, 2006Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 4, 2006Provider: repository / Type: Initial release
Revision 1.1Apr 30, 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 1.4Apr 2, 2014Group: Structure summary
Revision 1.5Oct 25, 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_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 / _struct_ref_seq_dif.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Caspase-3
B: Caspase-3
I: PHQ-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE


Theoretical massNumber of molelcules
Total (without water)29,1683
Polymers29,1683
Non-polymers00
Water6,035335
1
A: Caspase-3
B: Caspase-3
I: PHQ-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE

A: Caspase-3
B: Caspase-3
I: PHQ-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE


Theoretical massNumber of molelcules
Total (without water)58,3366
Polymers58,3366
Non-polymers00
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_656-x+1,y,-z+11
Buried area16910 Å2
ΔGint-88 kcal/mol
Surface area19540 Å2
MethodPISA, PQS
Unit cell
Length a, b, c (Å)67.650, 83.890, 96.160
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-392-

HOH

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Components

#1: Protein Caspase-3 / Caspase 3


Mass: 16524.814 Da / Num. of mol.: 1 / Fragment: Caspase-3 p17 subunit, residues 29-174
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pET11d / Production host: Escherichia coli (E. coli)
References: UniProt: P42574, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Protein Caspase-3 / Caspase 3


Mass: 11981.682 Da / Num. of mol.: 1 / Fragment: Caspase-3 p12 subunit, residues 175-277 / Mutation: D175A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pET11d / Production host: Escherichia coli (E. coli)
References: UniProt: P42574, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#3: Protein/peptide PHQ-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE / Z-DEVD-CMK


Type: Peptide-like / Class: Inhibitor / Mass: 661.486 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: chemically synthesized
References: N-[(benzyloxy)carbonyl]-L-alpha-aspartyl-L-alpha-glutamyl-N-[(1S)-1-(carboxymethyl)-3-chloro-2-oxopropyl]-L-valinamide
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 335 / Source method: isolated from a natural source / Formula: H2O
Compound detailsTHE UNBOUND INHIBITOR (CHAIN I) IS CARBOBENZOXY-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE. UPON REACTION ...THE UNBOUND INHIBITOR (CHAIN I) IS CARBOBENZOXY-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE. UPON REACTION WITH THE ENZYME CHLORINE DISSOCIATES AND THE INHIBITOR COVALENTLY BINDS TO THE SG CYS 163 A OF THE ENZYME FORMING A TETRAHEDRAL INTERMEDIATE.

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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: 2.35 Å3/Da / Density % sol: 47.73 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 4.75 / Details: pH 4.75, VAPOR DIFFUSION, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.8498 / Wavelength: 0.8498 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: May 29, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8498 Å / Relative weight: 1
ReflectionResolution: 1.06→20 Å / Num. all: 113110 / Num. obs: 113110 / % possible obs: 92 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.1 % / Rmerge(I) obs: 0.055 / Net I/σ(I): 7.9
Reflection shellResolution: 1.06→1.15 Å / Rmerge(I) obs: 0.366 / Mean I/σ(I) obs: 3.06 / % possible all: 89

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Processing

Software
NameClassification
XDSdata scaling
XSCALEdata scaling
AMoREphasing
SHELXL-97refinement
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1cp3

1cp3


Resolution: 1.06→20 Å / Num. parameters: 20202 / Num. restraintsaints: 24660 / Cross valid method: FREE R / σ(F): 0 / Stereochemistry target values: ENGH & HUBER
RfactorNum. reflection% reflectionSelection details
Rfree0.1747 2049 1.8 %RANDOM
Rwork0.142 ---
obs0.142 113110 89.9 %-
all-113110 --
Refine analyzeNum. disordered residues: 20 / Occupancy sum hydrogen: 1933 / Occupancy sum non hydrogen: 2362.5
Refinement stepCycle: LAST / Resolution: 1.06→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2029 0 0 335 2364
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONs_bond_d0.017
X-RAY DIFFRACTIONs_angle_d0.035
X-RAY DIFFRACTIONs_similar_dist0
X-RAY DIFFRACTIONs_from_restr_planes0.0301
X-RAY DIFFRACTIONs_zero_chiral_vol0.086
X-RAY DIFFRACTIONs_non_zero_chiral_vol0.113
X-RAY DIFFRACTIONs_anti_bump_dis_restr0.044
X-RAY DIFFRACTIONs_rigid_bond_adp_cmpnt0.006
X-RAY DIFFRACTIONs_similar_adp_cmpnt0.054
X-RAY DIFFRACTIONs_approx_iso_adps0

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