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- PDB-1nms: Caspase-3 tethered to irreversible inhibitor -

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Basic information

Entry
Database: PDB / ID: 1nms
TitleCaspase-3 tethered to irreversible inhibitor
ComponentsCaspase-3
KeywordsAPOPTOSIS / HYDROLASE / Caspase-3 / tether / irreversible / inhibitor
Function / homology
Function and homology information


caspase-3 / phospholipase A2 activator activity / Stimulation of the cell death response by PAK-2p34 / 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 / phospholipase A2 activator activity / Stimulation of the cell death response by PAK-2p34 / 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 / cellular response to staurosporine / cyclin-dependent protein serine/threonine kinase inhibitor activity / death-inducing signaling complex / Apoptosis induced DNA fragmentation / Apoptotic cleavage of cell adhesion proteins / Caspase activation via Dependence Receptors in the absence of ligand / SMAC, XIAP-regulated apoptotic response / Activation of caspases through apoptosome-mediated cleavage / Signaling by Hippo / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / axonal fasciculation / regulation of synaptic vesicle cycle / death receptor binding / fibroblast apoptotic process / epithelial cell apoptotic process / platelet formation / Other interleukin signaling / response to anesthetic / execution phase of apoptosis / negative regulation of cytokine production / positive regulation of amyloid-beta formation / Apoptotic cleavage of cellular proteins / negative regulation of B cell proliferation / pyroptotic inflammatory response / neurotrophin TRK receptor signaling pathway / negative regulation of activated T cell proliferation / response to tumor necrosis factor / negative regulation of cell cycle / T cell homeostasis / B cell homeostasis / Pyroptosis / cell fate commitment / regulation of macroautophagy / Caspase-mediated cleavage of cytoskeletal proteins / response to X-ray / response to amino acid / response to glucose / response to UV / keratinocyte differentiation / Degradation of the extracellular matrix / striated muscle cell differentiation / intrinsic apoptotic signaling pathway / response to glucocorticoid / protein maturation / erythrocyte differentiation / response to nicotine / hippocampus development / apoptotic signaling pathway / enzyme activator activity / response to hydrogen peroxide / protein catabolic process / sensory perception of sound / regulation of protein stability / protein processing / response to wounding / neuron differentiation / response to estradiol / peptidase activity / positive regulation of neuron apoptotic process / heart development / protease binding / neuron apoptotic process / response to lipopolysaccharide / aspartic-type endopeptidase activity / learning or memory / response to hypoxia / postsynaptic density / response to xenobiotic stimulus / cysteine-type endopeptidase activity / neuronal cell body / apoptotic process / DNA damage response / protein-containing complex binding / glutamatergic synapse / proteolysis / nucleoplasm / nucleus / cytoplasm / cytosol
Similarity search - Function
Rossmann fold - #1460 / Peptidase C14 family / 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 ...Rossmann fold - #1460 / Peptidase C14 family / 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 / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-161 / Caspase-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsErlanson, D.A. / Lam, J. / Wiesmann, C. / Luong, T.N. / Simmons, R.L. / DeLano, W.L. / Choong, I.C. / Flanagan, W.M. / Lee, D. / O'Brian, T.
Citation
#1: Journal: J.Med.Chem. / Year: 2002
Title: Identification of Potent and Selective Small-Molecule Inhibitors of Caspase-3 through the Use of Extended Tethering and Structure-Based Drug Design
Authors: Choong, I.C. / Lew, W. / Lee, D. / Pham, P. / Burdett, M.T. / Lam, J.W. / Wiesmann, C. / Luong, T.N. / Fahr, B. / O'Brian, T.
History
DepositionJan 10, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 11, 2003Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Aug 16, 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_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_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Caspase-3
B: Caspase-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,9664
Polymers57,0372
Non-polymers9292
Water10,575587
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6500 Å2
ΔGint-25 kcal/mol
Surface area19230 Å2
MethodPISA
2
A: Caspase-3
B: Caspase-3
hetero molecules

A: Caspase-3
B: Caspase-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,9328
Polymers114,0744
Non-polymers1,8584
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area15580 Å2
ΔGint-59 kcal/mol
Surface area35860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)123.450, 70.952, 95.860
Angle α, β, γ (deg.)90.00, 136.42, 90.00
Int Tables number5
Cell settingmonoclinic
Space group name H-MC121

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Components

#1: Protein Caspase-3 / E.C.3.4.22.- / Apopain / Cysteine protease CPP32 / Yama protein / CPP-32 / CASP-3 / SREBP cleavage activity 1 / SCA-1


Mass: 28518.500 Da / Num. of mol.: 2 / Fragment: large subunit
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
#2: Chemical ChemComp-161 / 5-[4-(1-CARBOXYMETHYL-2-OXO-PROPYLCARBAMOYL)-BENZYLSULFAMOYL]-2-HYDROXY-BENZOIC ACID


Mass: 464.446 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H20N2O9S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 587 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.28 Å3/Da / Density % sol: 45.7 %
Crystal grow
*PLUS
Temperature: 20 ℃ / pH: 8.5 / Method: vapor diffusion, hanging drop
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
15-10 mg/mlprotein1drop
210 mMTris1droppH8.5
3100 mMsodium citrate1reservoirpH5.9
44 %(v/v)glycerol1reservoir
510-20 %(w/v)PEG60001reservoir
610 mMdithiothreitol1reservoir

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 1.08 Å
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Nov 1, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.08 Å / Relative weight: 1
ReflectionResolution: 1.65→30 Å / Num. obs: 62041 / % possible obs: 98.9 % / Observed criterion σ(I): -3 / Rsym value: 0.053 / Net I/σ(I): 12.2
Reflection
*PLUS
Highest resolution: 1.7 Å / Lowest resolution: 20 Å / % possible obs: 98.8 % / Rmerge(I) obs: 0.053

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
REFMAC5refinement
CCP4(SCALA)data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1CP3

1cp3


Resolution: 1.7→20 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.954 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.18335 3135 5.1 %RANDOM
Rwork0.15102 ---
all0.15266 58906 --
obs0.15266 58906 98.83 %-
Solvent computationShrinkage radii: 0.8 Å / Solvent model: MASK
Displacement parametersBiso mean: 16.586 Å2
Baniso -1Baniso -2Baniso -3
1-0.79 Å20 Å20.64 Å2
2---0.02 Å20 Å2
3---0.16 Å2
Refinement stepCycle: LAST / Resolution: 1.7→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3880 0 64 587 4531
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0214026
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.7351.9625416
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1523476
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.79915744
X-RAY DIFFRACTIONr_chiral_restr0.1540.2576
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.023052
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2370.31857
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1580.5577
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1640.359
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1860.531
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_mcbond_it2.742.52384
X-RAY DIFFRACTIONr_mcangle_it4.36353846
X-RAY DIFFRACTIONr_scbond_it4.3082.51642
X-RAY DIFFRACTIONr_scangle_it6.32251570
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.7→1.735 Å / Total num. of bins used: 25 /
RfactorNum. reflection
Rfree0.278 174
Rwork0.223 3436
Refinement
*PLUS
Highest resolution: 1.7 Å / Lowest resolution: 20 Å / Rfactor Rfree: 0.183 / Rfactor Rwork: 0.151
Solvent computation
*PLUS
Displacement parameters
*PLUS

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