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- PDB-3h0e: 3,4-Dihydropyrimido(1,2-a)indol-10(2H)-ones as Potent Non-Peptidi... -

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Basic information

Entry
Database: PDB / ID: 3h0e
Title3,4-Dihydropyrimido(1,2-a)indol-10(2H)-ones as Potent Non-Peptidic Inhibitors of Caspase-3
ComponentsCaspase-3Caspase 3
KeywordsHYDROLASE / Caspase-3 / protein-inhibitor complex / apoptosis / Cytoplasm / Phosphoprotein / Polymorphism / Protease / S-nitrosylation / Thiol protease / Zymogen
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
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 ...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 / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-H0E / Caspase-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.997 Å
AuthorsXu, W.
CitationJournal: Bioorg.Med.Chem. / Year: 2009
Title: 3,4-Dihydropyrimido(1,2-a)indol-10(2H)-ones as potent non-peptidic inhibitors of caspase-3
Authors: Havran, L.M. / Chong, D.C. / Childers, W.E. / Dollings, P.J. / Dietrich, A. / Harrison, B.L. / Marathias, V. / Tawa, G. / Aulabaugh, A. / Cowling, R. / Kapoor, B. / Xu, W. / Mosyak, L. / ...Authors: Havran, L.M. / Chong, D.C. / Childers, W.E. / Dollings, P.J. / Dietrich, A. / Harrison, B.L. / Marathias, V. / Tawa, G. / Aulabaugh, A. / Cowling, R. / Kapoor, B. / Xu, W. / Mosyak, L. / Moy, F. / Hum, W.T. / Wood, A. / Robichaud, A.J.
History
DepositionApr 9, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 17, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,6344
Polymers58,7232
Non-polymers9112
Water5,008278
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4680 Å2
ΔGint-24 kcal/mol
Surface area18580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)125.739, 69.940, 88.797
Angle α, β, γ (deg.)90.00, 130.08, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Caspase-3 / Caspase 3 / CASP-3 / Apopain / Cysteine protease CPP32 / CPP-32 / Yama protein / SREBP cleavage activity 1 / ...CASP-3 / Apopain / Cysteine protease CPP32 / CPP-32 / Yama protein / SREBP cleavage activity 1 / SCA-1 / Caspase-3 subunit p17 / Caspase-3 subunit p12


Mass: 29361.396 Da / Num. of mol.: 2 / Fragment: Subunits p17 and p12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP3, CPP32 / Production host: Escherichia coli (E. coli) / References: UniProt: P42574, caspase-3
#2: Chemical ChemComp-H0E / (10S)-3,3-dimethyl-8-{[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl}-2,3,4,10-tetrahydropyrimido[1,2-a]indol-10-ol


Mass: 455.570 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H29N3O4S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 278 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsTHE ORIGINAL REAGENT HAS A DOUBLE BOND BETWEEN O1 AND C5. WHEN THE REAGENT MAKES A COVALENT BOND ...THE ORIGINAL REAGENT HAS A DOUBLE BOND BETWEEN O1 AND C5. WHEN THE REAGENT MAKES A COVALENT BOND WITH CYS, THE DOUBLE BOND OPENS TO FORM A TETRAHEDRAL CONFIGURATION.

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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: 2.54 Å3/Da / Density % sol: 51.65 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.9
Details: 0.1M NaCitrate, pH 5.9, 10mM L-Cys, 5% Glycerol, 10% PEG3350, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 143 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jul 1, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.997→20 Å / Num. all: 40063 / Num. obs: 38681 / % possible obs: 96.55 % / Biso Wilson estimate: 25.27 Å2 / Rmerge(I) obs: 0.038 / Net I/σ(I): 27.4
Reflection shellResolution: 1.997→2.07 Å / Rmerge(I) obs: 0.228 / Mean I/σ(I) obs: 4.66 / % possible all: 97.1

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
AMoREphasing
PHENIX(phenix.refine)refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.997→19.817 Å / SU ML: 0.21 / σ(F): 0.01 / Phase error: 21.37 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2004 1179 3.05 %random
Rwork0.1769 ---
obs0.1776 38681 96.55 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 63.458 Å2 / ksol: 0.387 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--3.9907 Å2-0 Å2-12.9325 Å2
2---0.7066 Å20 Å2
3---4.6973 Å2
Refinement stepCycle: LAST / Resolution: 1.997→19.817 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3837 0 64 278 4179
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0033989
X-RAY DIFFRACTIONf_angle_d0.7985376
X-RAY DIFFRACTIONf_dihedral_angle_d15.591468
X-RAY DIFFRACTIONf_chiral_restr0.057570
X-RAY DIFFRACTIONf_plane_restr0.003679
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.997-2.08790.22791180.21394275X-RAY DIFFRACTION89
2.0879-2.19790.2441460.20454532X-RAY DIFFRACTION94
2.1979-2.33540.22421560.18244626X-RAY DIFFRACTION96
2.3354-2.51530.23161480.18074674X-RAY DIFFRACTION97
2.5153-2.76790.20911620.18764779X-RAY DIFFRACTION98
2.7679-3.1670.20521580.1874802X-RAY DIFFRACTION99
3.167-3.98470.17851500.16354869X-RAY DIFFRACTION100
3.9847-19.81820.17941410.1624945X-RAY DIFFRACTION100
Refinement TLS params.

S33: 0 Å ° / Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.75910.38280.39340.78450.12221.17550.00190.2238-0.2539-0.07090.11830.14120.0296-0.02960.1955-0.019-0.00210.2012-0.01820.199239.206642.438111.8965
21.92040.33120.36320.92760.13650.9762-0.1497-0.10850.19650.02430.09920.0315-0.13460.0840.18450.00350.01790.1679-0.03420.161754.270556.865526.0164
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain A
2X-RAY DIFFRACTION2chain B

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