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- PDB-1rhq: CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-3 WITH A BROMOMETHOXY... -

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Basic information

Entry
Database: PDB / ID: 1rhq
TitleCRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-3 WITH A BROMOMETHOXYPHENYL INHIBITOR
Components(Caspase-3Caspase 3) x 2
KeywordsHYDROLASE/hydrolase inhibitor / CYSTEINE PROTEASE / CASPASE-3 / APOPAIN / CPP32 / YAMA / 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
(3S)-5-(benzylsulfanyl)-3-({N-[(5-bromo-2-methoxyphenyl)acetyl]-L-valyl}amino)-4-oxopentanoic acid / Chem-0ZZ / Caspase-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsBecker, J.W. / Rotonda, J. / Soisson, S.M.
CitationJournal: J.Med.Chem. / Year: 2004
Title: Reducing the Peptidyl Features of Caspase-3 Inhibitors: A Structural Analysis.
Authors: Becker, J.W. / Rotonda, J. / Soisson, S.M. / Aspiotis, R. / Bayly, C. / Francoeur, S. / Gallant, M. / Garcia-Calvo, M. / Giroux, A. / Grimm, E. / Han, Y. / McKay, D. / Nicholson, D.W. / ...Authors: Becker, J.W. / Rotonda, J. / Soisson, S.M. / Aspiotis, R. / Bayly, C. / Francoeur, S. / Gallant, M. / Garcia-Calvo, M. / Giroux, A. / Grimm, E. / Han, Y. / McKay, D. / Nicholson, D.W. / Peterson, E. / Renaud, J. / Roy, S. / Thornberry, N. / Zamboni, R.
History
DepositionNov 14, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 11, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 29, 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 1.4Jan 22, 2014Group: Other
Revision 1.5Oct 11, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.6Dec 21, 2022Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / struct_conn / struct_ref_seq_dif / struct_site
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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.7Sep 20, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.8Mar 13, 2024Group: Source and taxonomy / Structure summary / Category: entity / pdbx_entity_src_syn / Item: _entity.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
D: Caspase-3
E: Caspase-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,2646
Polymers57,1014
Non-polymers1,1632
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13370 Å2
ΔGint-74 kcal/mol
Surface area17670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.300, 96.900, 70.900
Angle α, β, γ (deg.)90.00, 128.06, 90.00
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(0.22793, -0.007849, 0.973646), (-0.007261, -0.999953, -0.006361), (0.973651, -0.005619, -0.227976)-47.6342, 16.0809, 60.2584
DetailsThe asymmetric unit contains one biological assembly.

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Components

#1: Protein Caspase-3 / Caspase 3 / Cysteine protease CPP32 / Yama protein / CPP-32 / Apopain / CASP-3 / SREBP cleavage activity 1 / SCA-1


Mass: 16639.902 Da / Num. of mol.: 2 / Fragment: P17 SUBUNIT
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP3, CPP32 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P42574, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Protein Caspase-3 / Caspase 3 / Cysteine protease CPP32 / Yama protein / CPP-32 / Apopain / CASP-3 / SREBP cleavage activity 1 / SCA-1


Mass: 11910.604 Da / Num. of mol.: 2 / Fragment: P12 SUBUNIT
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP3, CPP32 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P42574, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#3: Chemical ChemComp-0ZZ / 5-S-benzyl-3-({N-[(5-bromo-2-methoxyphenyl)acetyl]-L-valyl}amino)-2,3-dideoxy-5-thio-D-erythro-pentonic acid


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 581.519 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H33BrN2O6S
Details: BOP covalently bound to the N-terminus, PTF covalently bound to the C-terminus The inhibitor was chemically synthesized.
References: (3S)-5-(benzylsulfanyl)-3-({N-[(5-bromo-2-methoxyphenyl)acetyl]-L-valyl}amino)-4-oxopentanoic acid
Nonpolymer detailsTHE INHIBITOR BINDS TO THE CATALYTIC CYS 285 IN CHAINS A AND D VIA HEMITHIOACETAL LINKAGES

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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: 2.59 Å3/Da / Density % sol: 52.48 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.93
Details: 7.8% PEG-6000, 100 mM citrate, 120 mM ZnCl(2), 10 mM DTT, 3 mM NaN(3), pH 4.93, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 293 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.54178 Å
DetectorType: SIEMENS / Detector: AREA DETECTOR / Date: Apr 5, 1998
RadiationMonochromator: Graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.999→20 Å / Num. all: 11870 / Num. obs: 11487 / % possible obs: 96.77 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 1.39 % / Rmerge(I) obs: 0.061 / Net I/σ(I): 5.22
Reflection shellResolution: 2.999→3.106 Å / Redundancy: 1.2 % / Rmerge(I) obs: 0.163 / Mean I/σ(I) obs: 2.03 / Num. unique all: 1034 / % possible all: 88.7

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Processing

Software
NameVersionClassification
CNX2002refinement
X-GENdata reduction
SAINTV. 4.050data scaling
X-PLORphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Protein part of 1pau.pdb

1pau


Resolution: 3→20 Å / Rfactor Rfree error: 0.011 / Data cutoff high absF: 19655.73 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.354 1020 10.2 %RANDOM
Rwork0.273 ---
all-9964 --
obs-9964 84.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 10 Å2 / ksol: 0.18333 e/Å3
Displacement parametersBiso mean: 11.8 Å2
Baniso -1Baniso -2Baniso -3
1-6.56 Å20 Å24.48 Å2
2--2.42 Å20 Å2
3----8.97 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.62 Å0.45 Å
Luzzati d res low-5 Å
Luzzati sigma a0.75 Å0.62 Å
Refinement stepCycle: LAST / Resolution: 3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3740 0 72 0 3812
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_angle_deg1.6
X-RAY DIFFRACTIONc_dihedral_angle_d24.2
X-RAY DIFFRACTIONc_improper_angle_d0.81
X-RAY DIFFRACTIONc_mcbond_it6.11.5
X-RAY DIFFRACTIONc_mcangle_it9.472
X-RAY DIFFRACTIONc_scbond_it7.32
X-RAY DIFFRACTIONc_scangle_it10.782.5
Refine LS restraints NCSNCS model details: CONSTR
LS refinement shellResolution: 3→3.19 Å / Rfactor Rfree error: 0.036 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.411 132 9.1 %
Rwork0.349 1312 -
obs-1228 73.7 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARWATER.TOP
X-RAY DIFFRACTION3ION.PARAMION.TOP
X-RAY DIFFRACTION4PARAM.ICETOP_NEW.ICE

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